• 40
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
IMMP2L (HGNC:14598) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
inner mitochondrial membrane peptidase subunit 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
IMMP2L-IT1
Alias symbols
IMP2
%HI
4.25(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.01(Read more about gnomAD pLI score)
LOEUF
1.2(Read more about gnomAD LOEUF score)
Cytoband
7q31.1
Genomic Coordinates
GRCh37/hg19: chr7:110302700-111202548 NCBI Ensembl UCSC
GRCh38/hg38: chr7:110662644-111562492 NCBI Ensembl UCSC
MANE Select Transcript
NM_032549.4 ENST00000405709.7 (Read more about MANE Select)
Function
Catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space. Known to process the nuclear encoded protein DIABLO. {ECO:0000269|PubMed:15814844}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-21638
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Dosage Sensitivity Unlikely (40)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
04/12/2022

Haploinsufficiency (HI) Score Details

HI Score:
40
HI Evidence Strength:
Dosage Sensitivity Unlikely (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 25478008
    Gimelli et al (2014) describes four unrelated patients with inherited, overlapping 7q31.1 deletions/duplications disrupting the IMMP2L gene, all which were identified by array-CGH. Patient 1 is a 14-month old female who presented with psychomotor delay and nystagmus. She was found to have a 269.6-kb loss which includes exon 3 of IMMP2L; this loss was inherited from her healthy father. Patient 2 is a 5-year old male who presented with a psychomotor and language delay and eplilepsy. He was found to have a 152.7-kb loss which includes exons 1-3 of IMMP2L; this loss was inherited by his healthy father. Patient 3 is a 9-year old male who present with psychomotor and language delay, epilepsy, and hypotonia. He was found to have a 249.9-kb loss which includes exons 1-3 of IMMP2L; this loss was inherited by his healthy father. Patient 4 is a 10-month old male who presented with psychomotor and language delay and hypotonia. He was found to have a 370.7-kb gain which includes exon 6 of IMMP2L; this gain was inherited by his healthy father. In addition, a 171-kb gain which includes five genes (FOXK1, AP5Z1, RADIL, PAPOLB, MMD2) was inherited by his healthy mother.
  • PUBMED: 24549057
    Bertelsen et al (2014) performed chromosomal microarray on 188 unrelated patients with Tourette syndrome and identified seven patients with intragenic IMMP2L deletions (3.7%) which was found to be significantly higher (P=0.0447) when compared to a Danish control cohort (0.9%). Patient 1 was found to have a 331-kb deletion that included exons 1-3 of IMMP2L which was observed to be inherited from the father with dyslexia and temper. Patient 2 was found to have a 148-kb deletion that included exons 2-3 of IMMP2L which was observed to be inherited from the mother with tics and OCD. Patient 3 was found to have a 163-kb deletion that includes exon 3 which was observed to be inherited from an unaffected mother. In addition, a 120-kb paternal duplication which includes a portion of DISC1 was also observed. Patient 4 had a 191-kb deletion that included exon 3 of IMMP2L which was observed to be inherited from the father with OCD and stuttering. In addition, a 1.7-Mb paternal duplication which includes 5 genes was also observed. Patient 5 was found to have a 49-kb deletion that includes exon 3 of IMMP2L; inheritance is unknown. In addition, a 420-kb duplication which includes 2 genes was also observed. Patient 6 was found to have a 210-kb deletion that includes exon 3 of IMMP2L which was observed to be inherited from the father with stubbornness. Patient 7 was found to have a 143-kb deletion that includes exons 2-3 of IMMP2L which was observed to be inherited from the unaffected father. The authors suggest that intragenic deletions of IMMP2L may be genetic risk factors to Tourette syndrome.
  • PUBMED: 29152845
    Zhang et al (2017) conducted a meta-analysis to quantify the association of IMMP2L deletions with ASD using 100 unrelated trio families with an index proband with ASD (one affected proband and both unaffected parents), 5,568 ASD cases, and 10,279 ASD-unaffected controls. In the 100 trio ASD cohort three probands were observed to have a deletion of IMMP2L which included exons 1-3 (182-kb, 245-kb, and 201-kb, respectively). The deletion observed in case 1 was de novo while the deletion observed in case 2 and 3 were maternally inherited. The overall rates of IMMP2L deletions in ASD cases were 120 (2.16%) and 288 (2.52%) in controls. There was no significant difference between both cases and controls (P >0.05). In addition, there was no significant differences between cases and controls (P >0.05) when comparing the number of cases that had deletions disrupting the coding sequences of IMMP2L (0.86% in cases, 0.69% in controls). The authors conclude that, in summary, the meta-analysis did not indicate a general association between IMMP2L deletions and ASD.
  • PUBMED: 33849037
    Vasilyev et al (2021) describe 6 families* with deletions that included one or more of the first 3 exons of the IMMP2L gene with 4/6 deletions being of maternal origin. They assessed the expression of the IMMP2L gene in 2 families with maternally inherited deletions using microarrays to analyse the effect of differential methylation at CpG sites in the IMMP2L gene on the expression of this gene. Per the authors: "The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3** families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions." (*Three of the probands had other copy number changes/**1 proband had Prader-Willi syndrome)
HI Evidence Comments:
Although there have been reports of full and partial IMMP2L deletions in individuals with Tourette syndrome and/or developmental delay and disability, they have also been reported in individuals in the general population. Numerous deletions over this gene have been reported in population databases. While it is possible that factors such as incomplete penetrance or epigenetic modification/parent of origin effect could play a role in disease etiology, due to the overwhelming population evidence, the ClinGen Dosage Sensitivity working group is classifying this gene as "Dosage Sensitivity Unlikely." There is currently insufficient evidence to support IMMP2L haploinsufficiency at this time. Additional information includes: PMID 21386874: Patel et al (2011) describes an 18-year old male with Tourette syndrome-like tics, moderate learning difficulties, and severe speech difficulties. Chromosome analysis identified a de novo t(2;7)(p24.2;q31) in which follow-up array CGH identified a 7.25-Mb deletion from 7q31.1 to 7q31.2 (7:110,702,484-117,947,839). The deletion includes exons 1-3 of the IMMP2L gene and 21 additional HGNC genes. The translocation was determined to be a de novo finding following chromosome analysis of parental samples. PMID 11254443: Petek et al (2001) describes a 13-year old male with intellectual and developmental delay. Using DSM-III-R criteria the patient was diagnosed with Gilles de la Tourette syndrome (GTS). In addition to GTS features, such as in-voluntary motor and vocal tics, he had reduced speech development, depression, strabismus convergens, a mal-formed left ear, meatus acusticus stenosis, slight micro-genia, and considerable gynecomastia. This patient has also been described by Kroisel et al (2001, PMID: 11424142). Chromosome analysis identified a de novo dup(7)(q22.1q13.1). Florescence in situ hybridization (FISH) and Southern blot analysis identified the inverted duplicated region to be approximately 15-Mb in size. Through cloning and sequencing IMMP2L was determined to be disrupted, located at chromosome band 7q31. However, the 15-Mb duplicated region includes additional candidate genes. PMID 22102821: Giriranjan et al (2011) describes a male patient (sample 3437) with dyslexia who inherited a 471-kb deletion involving exons 2-3 of IMMP2L from an affected parent (text indicates mother while Figure 3c and Table 3 indicates father). This deletion has also been observed in two (out of 337) controls (Table 3). PMID 19546859: Elia et al (2010) identified a patient (subject 130_197_3) from a cohort of 335 individuals with ADHA with a ~250-kb deletion which includes intron 4 of IMMP2L (chr 7: 110,672,863-110,923,287). This deletion was not observed in a cohort of 2026 unrelated healthy individuals. It is assumed that this deletion was inherited from an affected parent.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
There is no evidence of triplosensitivity as of December 2021.

Genomic View

Select assembly: (NC_000007.13) (NC_000007.14)