rs72653796
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate
The NM_001171.6(ABCC6):c.2432C>T(p.Thr811Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,058 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T811R) has been classified as Pathogenic.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2432C>T | p.Thr811Met | missense_variant | 19/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.2090C>T | p.Thr697Met | missense_variant | 19/31 | ||
ABCC6 | NR_147784.1 | n.2452+1188C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2432C>T | p.Thr811Met | missense_variant | 19/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.2432C>T | p.Thr811Met | missense_variant, NMD_transcript_variant | 19/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.2415+1188C>T | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251356Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461866Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14AN XY: 727232
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152192Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Pathogenic, no assertion criteria provided | research | PXE International | Mar 01, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 811 of the ABCC6 protein (p.Thr811Met). This variant is present in population databases (rs72653796, gnomAD 0.01%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 16410789, 32873932). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433275). 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) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC6 function (PMID: 30154241). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at