rs527236051
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5
The NM_001171.6(ABCC6):c.4069C>T(p.Arg1357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,424 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1357Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.4069C>T | p.Arg1357Trp | missense_variant | 29/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.3727C>T | p.Arg1243Trp | missense_variant | 29/31 | ||
ABCC6 | NR_147784.1 | n.3731C>T | non_coding_transcript_exon_variant | 27/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.4069C>T | p.Arg1357Trp | missense_variant | 29/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000576204.6 | n.932C>T | non_coding_transcript_exon_variant | 2/2 | 5 | ||||
ABCC6 | ENST00000456970.6 | c.*1078C>T | 3_prime_UTR_variant, NMD_transcript_variant | 27/29 | 2 | ||||
ABCC6 | ENST00000622290.5 | c.*241C>T | 3_prime_UTR_variant, NMD_transcript_variant | 30/32 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152142Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000488 AC: 12AN: 245856Hom.: 0 AF XY: 0.0000525 AC XY: 7AN XY: 133402
GnomAD4 exome AF: 0.0000911 AC: 133AN: 1460166Hom.: 0 Cov.: 31 AF XY: 0.0000978 AC XY: 71AN XY: 726216
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152258Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4AN XY: 74440
ClinVar
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | research | PXE International | Mar 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jun 19, 2023 | - - |
not provided Pathogenic:1Benign:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1357 of the ABCC6 protein (p.Arg1357Trp). This variant is present in population databases (rs63750428, gnomAD 0.03%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 15645653, 16086317, 28912966). 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: 143119). 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. For these reasons, this variant has been classified as Pathogenic. - |
Likely benign, no assertion criteria provided | literature only | Department of Ophthalmology and Visual Sciences Kyoto University | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at