rs121918542
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2PM5PP5_Very_StrongBP4
The NM_002242.4(KCNJ13):c.484C>T(p.Arg162Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_002242.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ13 | NM_002242.4 | c.484C>T | p.Arg162Trp | missense_variant | 3/3 | ENST00000233826.4 | |
GIGYF2 | NM_001103146.3 | c.532+7354G>A | intron_variant | ENST00000373563.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ13 | ENST00000233826.4 | c.484C>T | p.Arg162Trp | missense_variant | 3/3 | 1 | NM_002242.4 | P1 | |
GIGYF2 | ENST00000373563.9 | c.532+7354G>A | intron_variant | 1 | NM_001103146.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 247900Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134414
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1450060Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 719102
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Snowflake vitreoretinal degeneration Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Molecular Genetics, University of Zurich | Jan 30, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | May 05, 2022 | This sequence change is predicted to replace arginine with tryptophan at codon 162 of the KCNJ13 protein, p.(Arg162Trp). The arginine residue is evolutionarily conserved in vertebrates (100 vertebrates, UCSC), and is located inward rectifier potassium channel transmembrane domain. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a single individual in a large population cohort (rs121918542, 1/247,900 alleles in gnomAD v2.1). The variant is present in at least three individuals with snowflake vitreoretinal degeneration (SVD) or macular dystrophy, and segregates with SVD over four generations (PMID: 18179896, 15557460, 33546218; Royal Melbourne Hospital). Additionally, in vitro functional assays demonstrate that the variant suppresses the potassium channel activity with a dominant-negative effect (PMID: 18179896, 23255580). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | 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 KCNJ13 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ13 function (PMID: 18179896, 23255580, 23977131). ClinVar contains an entry for this variant (Variation ID: 6585). This missense change has been observed in individual(s) with snowflake vitreoretinal degeneration (PMID: 18179896). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918542, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the KCNJ13 protein (p.Arg162Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at