rs797045213
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000352.6(ABCC8):āc.563A>Gā(p.Asn188Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.563A>G | p.Asn188Ser | missense_variant | 4/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.563A>G | p.Asn188Ser | missense_variant | 4/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1453258Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2AN XY: 721706
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2019 | Variant summary: ABCC8 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 235752 control chromosomes (gnomAD). c.563A>G has been reported in the literature in multiple individuals affected with Congenital or Familial Hyperinsulinism (Shyng_1998, Nestorowicz_1998, Christesen_2001, Del Roio Liberatore_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Shyng_2008, found the variant to form channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide. However, the authors do indicate the variant could be playing a role in transcription, translation, trafficking or stability of protein, where were not assessed. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 18, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. ClinVar contains an entry for this variant (Variation ID: 210082). This missense change has been observed in individual(s) with autosomal recessive diffuse or focal hyperinsulinism (PMID: 15562009, 16429405, 24434300, 24686051, 28442472). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the ABCC8 protein (p.Asn188Ser). - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 16, 2017 | - - |
Type 2 diabetes mellitus Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Hereditary hyperinsulinism Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 04, 2021 | - - |
Diabetes mellitus, permanent neonatal 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | May 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at