rs72657695
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_ModeratePP5_Moderate
The ENST00000205557.12(ABCC6):āc.3188T>Gā(p.Leu1063Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,564 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1063P) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000205557.12 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3188T>G | p.Leu1063Arg | missense_variant | 23/31 | ENST00000205557.12 | NP_001162.5 | |
ABCC6 | NM_001351800.1 | c.2846T>G | p.Leu949Arg | missense_variant | 23/31 | NP_001338729.1 | ||
ABCC6 | NR_147784.1 | n.3050T>G | non_coding_transcript_exon_variant | 22/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3188T>G | p.Leu1063Arg | missense_variant | 23/31 | 1 | NM_001171.6 | ENSP00000205557 | P1 | |
ABCC6 | ENST00000622290.5 | c.3188T>G | p.Leu1063Arg | missense_variant, NMD_transcript_variant | 23/32 | 5 | ENSP00000483331 | |||
ABCC6 | ENST00000456970.6 | c.*397T>G | 3_prime_UTR_variant, NMD_transcript_variant | 22/29 | 2 | ENSP00000405002 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251214Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461438Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726990
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1063 of the ABCC6 protein (p.Leu1063Arg). This variant is present in population databases (rs72657695, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of pseudoxanthoma elasticum (PMID: 16835894, 20801516, 32873932, 33812167; Invitae). 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: 433304). 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%. 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 02, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at