rs151344624
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_000352.6(ABCC8):โc.4160_4162delโ(p.Phe1387del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,592,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F1387F) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.4160_4162del | p.Phe1387del | inframe_deletion | 34/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.4160_4162del | p.Phe1387del | inframe_deletion | 34/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000233 AC: 5AN: 214572Hom.: 0 AF XY: 0.0000174 AC XY: 2AN XY: 115018
GnomAD4 exome AF: 0.00000903 AC: 13AN: 1439950Hom.: 0 AF XY: 0.0000112 AC XY: 8AN XY: 713640
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 04, 2019 | NM_000352.3(ABCC8):c.4160_4162delTCT(F1387del) is classified as pathogenic in the context of ABCC8-related familial hyperinsulinism. Sources cited for classification include the following: PMID 9648840, 21716120, 9618169, 11999683, 11226335, 10447255 and 8923011. Classification of NM_000352.3(ABCC8):c.4160_4162delTCT(F1387del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Feb 08, 2022 | - - |
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | May 27, 2024 | This variant is found to be a potent moderate impact, deleterious variant and sufficient scientific evidence to support gene-disease correlation. This is found more frequently in congenital Hyperinsulinism cases as per recent evidence as well. However, since this is not a high impact variant and has limited evidence, this variant is reclassified as Uncertain risk allele only. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Aug 16, 2023 | The p.Phe1387del variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 11999683, 33861964, 23327786, 8923011, 9618169, 31997554, 9648840, 23275527), and has been identified in 0.06% (6/9450) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151344624). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 196880) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 7 were compound heterozygotes that carried a reported pathogenic variant in unknown phase, which increases the likelihood that the p.Phe1387del variant is pathogenic (Variation ID: 9088; PMID: 8923011). In vitro functional studies provide some evidence that the p.Phe1387del variant may impact protein function (PMID: 11226335, 8923011, 9648840). However, these types of assays may not accurately represent biological function. This variant is a deletion of 1 amino acid at position 1387 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PS3, PM4_supporting (Richards 2015). - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This variant, c.4160_4162del, results in the deletion of 1 amino acid(s) of the ABCC8 protein (p.Phe1387del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771251369, gnomAD 0.04%). This variant has been observed in individuals with autosomal recessive hyperinsulinism and/or hyperinsulinism (PMID: 8923011, 9618169, 23275527). It has also been observed to segregate with disease in related individuals. This variant is also known as delF1388. ClinVar contains an entry for this variant (Variation ID: 196880). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ABCC8 function (PMID: 8923011, 11226335). For these reasons, this variant has been classified as Pathogenic. - |
Familial hyperinsulinism Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2016 | - - |
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 21, 2023 | - - |
Hereditary hyperinsulinism Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
ABCC8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 13, 2024 | The ABCC8 c.4160_4162delTCT variant is predicted to result in an in-frame deletion (p.Phe1387del). This variant has been reported in the literature as delta F1388 and is a known founder variant within the Ashkenazi Jewish population (De Franco et al. 2020. PubMed ID: 32027066; Glaser et al. 1999. PubMed ID: 10447255). This variant has been documented in the homozygous and compound heterozygous states in many individuals with familial hyperinsulinism (Nestorowicz et al. 1996. PubMed ID: 8923011; Cartier et al. 2001. PubMed ID: 11226335; Nestorowicz et al. 1998. PubMed ID: 9618169). Functional analysis shows that this variant impacts both membrane trafficking and activity of the potassium channel (Cartier et al. 2001. PubMed ID: 11226335; Shyng et al. 1998. PubMed ID: 9648840). This variant is reported in 0.063% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. - |
Maturity onset diabetes mellitus in young Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | May 27, 2024 | This variant is found to be a potent moderate impact, deleterious variant with a sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at