rs1411638309
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000352.6(ABCC8):c.4612C>T(p.Arg1538Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000548 in 1,458,576 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1538R) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 stop_gained
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.4612C>T | p.Arg1538Ter | stop_gained | 39/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.4612C>T | p.Arg1538Ter | stop_gained | 39/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1458576Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4AN XY: 725602
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ABCC8 protein in which other variant(s) (p.Leu1543Pro) have been determined to be pathogenic (PMID: 11867634, 15562009, 23275527). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 556392). This variant has not been reported in the literature in individuals affected with ABCC8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1538*) in the ABCC8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the ABCC8 protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2022 | Identified as heterozygous in a patient with hyperinsulinism in published literature (De Franco et al., 2020); Nonsense variant predicted to result in protein truncation, as the last 44 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32027066) - |
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 29, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at