chr16-16187193-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5PP3_StrongPP5_Moderate
The NM_001171.6(ABCC6):c.1798C>T(p.Arg600Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,516 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. R600L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.1798C>T | p.Arg600Cys | missense_variant | 14/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.1456C>T | p.Arg486Cys | missense_variant | 14/31 | ||
ABCC6 | NR_147784.1 | n.1835C>T | non_coding_transcript_exon_variant | 14/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.1798C>T | p.Arg600Cys | missense_variant | 14/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.1798C>T | p.Arg600Cys | missense_variant, NMD_transcript_variant | 14/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.1798C>T | p.Arg600Cys | missense_variant, NMD_transcript_variant | 14/29 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249816Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135306
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461374Hom.: 0 Cov.: 36 AF XY: 0.0000193 AC XY: 14AN XY: 726984
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 600 of the ABCC6 protein (p.Arg600Cys). This variant is present in population databases (rs72653777, gnomAD 0.03%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 15459974, 20075945, 32873932). ClinVar contains an entry for this variant (Variation ID: 433243). 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%. This variant disrupts the p.Arg600 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18513494). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1
Uncertain significance, no assertion criteria provided | research | PXE International | Feb 16, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at