rs121918542

Positions:

• chr2-232768790-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNJ13 NM_002242.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.04

Genes affected

KCNJ13 (HGNC:6259): (potassium inwardly rectifying channel subfamily J member 13) This gene encodes a member of the inwardly rectifying potassium channel family of proteins. Members of this family form ion channel pores that allow potassium ions to pass into a cell. The encoded protein belongs to a subfamily of low signal channel conductance proteins that have a low dependence on potassium concentration. Mutations in this gene are associated with snowflake vitreoretinal degeneration. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-232768789-C-T is described in Lovd as [Likely_pathogenic].
• PP5: Variant 2-232768790-G-A is Pathogenic according to our data. Variant chr2-232768790-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232768790-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-232768790-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3361854). . Strength limited to SUPPORTING due to the PP5.

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: 1 AN: 247900 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450060 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PROVEAN	Benign	0.23	N
REVEL	Uncertain	0.41
Sift	Benign	0.053	T
Vest4		0.45
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.64
ClinPred		1.0	D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918542; hg19: chr2-233633500; COSMIC: COSV52085600; COSMIC: COSV52085600;