chr16-16178871-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_001171.6(ABCC6):c.2342C>T(p.Ala781Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A781A) has been classified as Likely benign.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2342C>T | p.Ala781Val | missense_variant | 18/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.2000C>T | p.Ala667Val | missense_variant | 18/31 | ||
ABCC6 | NR_147784.1 | n.2379C>T | non_coding_transcript_exon_variant | 18/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2342C>T | p.Ala781Val | missense_variant | 18/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.2342C>T | p.Ala781Val | missense_variant, NMD_transcript_variant | 18/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.2342C>T | p.Ala781Val | missense_variant, NMD_transcript_variant | 18/29 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251006Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135784
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461586Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11AN XY: 727106
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with pseudoxanthoma elasticum in published literature (Chassaing et al., 2005); however information about a second variant was not provided; In vitro functional analysis showed that A781V mutant produced <20% of the wild type galactosidase activity, which likely results from changes in folding and structure of the domain; however A781V showed similar intracellular trafficking to wild-type protein, and in the context of the full protein, showed more efficient folding than the isolated NBD domain; This variant is associated with the following publications: (PMID: 15894595, 30154241, 23485117) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 781 of the ABCC6 protein (p.Ala781Val). This variant is present in population databases (rs72653791, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of pseudoxanthoma elasticum (PMID: 15894595). ClinVar contains an entry for this variant (Variation ID: 433273). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC6 function (PMID: 30154241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1
Uncertain significance, no assertion criteria provided | research | PXE International | Feb 04, 2021 | - - |
ABCC6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 21, 2023 | The ABCC6 c.2342C>T variant is predicted to result in the amino acid substitution p.Ala781Val. This variant was reported in an individual with pseudoxanthoma elasticum; however, detailed clinical and genetic information were not provided (Chassaing et al 2005. PubMed ID: 15894595). Structural biology studies indicated that this variant may result in partial loss-of-function, but the clinical validity of these studies has not been well established (Ran Y et al 2018. PubMed ID: 30154241). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16272728-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 05, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at