rs72559716
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000352.6(ABCC8):c.4411G>C(p.Asp1471His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1471N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000352.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.4411G>C | p.Asp1471His | missense_variant, splice_region_variant | 36/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.4411G>C | p.Asp1471His | missense_variant, splice_region_variant | 36/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1417356Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2AN XY: 700790
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 04, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp1471 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17466004, 18988933, 30352420, 30354297). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (ExAC no frequency). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects ABCC8 protein function (PMID: 17575084). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is also known as p.Asp1472His. This variant has been observed in individuals with congenital hyperinsulinism (PMID: 15562009, 23275527). This sequence change replaces aspartic acid with histidine at codon 1471 of the ABCC8 protein (p.Asp1471His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.