chr16-16178919-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_001171.6(ABCC6):c.2294G>A(p.Arg765Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,428 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. R765G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001171.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2294G>A | p.Arg765Gln | missense_variant | 18/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.1952G>A | p.Arg651Gln | missense_variant | 18/31 | ||
ABCC6 | NR_147784.1 | n.2331G>A | non_coding_transcript_exon_variant | 18/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2294G>A | p.Arg765Gln | missense_variant | 18/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.2294G>A | p.Arg765Gln | missense_variant, NMD_transcript_variant | 18/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.2294G>A | p.Arg765Gln | missense_variant, NMD_transcript_variant | 18/29 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250548Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135656
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461244Hom.: 0 Cov.: 36 AF XY: 0.0000193 AC XY: 14AN XY: 726930
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 765 of the ABCC6 protein (p.Arg765Gln). This variant is present in population databases (rs67561842, gnomAD 0.02%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 12673275, 30805891). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30337). 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). This variant disrupts the p.Arg765 amino acid residue in ABCC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18157818; Invitae). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2
Pathogenic, criteria provided, single submitter | research | PXE International | Mar 01, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
Arterial calcification, generalized, of infancy, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at