rs397514673

Variant names:

• chr1-160042009-C-T
• rs397514673
• NM_002241.5:c.524G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PP2 PP3_Strong PP5

The NM_002241.5(KCNJ10):​c.524G>A​(p.Arg175Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,418,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.91
• Publications: 19 publications found

Genes affected

KCNJ10 (HGNC:6256): (potassium inwardly rectifying channel subfamily J member 10) This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]

KCNJ10 Gene-Disease associations (from GenCC):

• EAST syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• enlarged vestibular aqueduct syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_002241.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 2.7053 (below the threshold of 3.09). GenCC associations: The gene is linked to EAST syndrome, enlarged vestibular aqueduct syndrome, Pendred syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-160042009-C-T is Pathogenic according to our data. Variant chr1-160042009-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41471.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ10	NM_002241.5	c.524G>A	p.Arg175Gln	missense_variant	Exon 2 of 2	ENST00000644903.1	NP_002232.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1	c.524G>A	p.Arg175Gln	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000918 AC: 2 AN: 217936 AF XY: 0.00000865

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000998

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000635 AC: 9 AN: 1418218 Hom.: 0 Cov.: 32 AF XY: 0.0000100 AC XY: 7 AN XY: 699508

African (AFR) AF: 0.00 AC: 0 AN: 32488

American (AMR) AF: 0.0000242 AC: 1 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00 AC: 0 AN: 78146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.00000735 AC: 8 AN: 1088534

Other (OTH) AF: 0.00 AC: 0 AN: 58392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

EAST syndrome Pathogenic:1 Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 175 of the KCNJ10 protein (p.Arg175Gln). This variant is present in population databases (rs397514673, gnomAD 0.006%). This missense change has been observed in individual(s) with EAST syndrome (PMID: 20651251). ClinVar contains an entry for this variant (Variation ID: 41471). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNJ10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 20651251). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Aug 25, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R175Q variant (also known as c.524G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 524. The arginine at codon 175 is replaced by glutamine, an amino acid with highly similar properties. In one study, this variant was detected as homozygous in an individual with a diagnosis of EAST syndrome who had epilepsy, ataxia, sensorineural deafness, hypomagnesemia, and hypokalemia. In addition, authors of this study performed functional studies showing that this alteration causes a marked impairment of channel function, a decrease in current, and a remarkable shift of pH sensitivity (Reichold M et al. Proc. Natl. Acad. Sci. U.S.A., 2010 Aug;107:14490-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Jul 16, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change, c.524G>A, in exon 2 results in an amino acid change, p.Arg175Gln. This has been previously described in the homozygous state a patient with ataxia, infantile onset epilepsy, sensorineural hearing loss and biochemical studies consistent with hypomagnesemia and hypokalemia (Reichold et al., 2010). In vitro functional expression assays showed that this variant severely impaired Kir4.1 channel activity through reducing channel open probability and PIP2 affinity which is important for channel activity. These results were suggestive of loss of channel function (Reichold et al., 2010). This particular sequence change has been described in the gnomAD database in two individuals in the heterozygous state which corresponds to a population frequency of 0.00092% (rs397514673). The p.Arg175Gln change affects a highly conserved amino acid residue located in a domain of the KCNJ10 protein that is known to be functional. The p.Arg175Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These evidences indicate that this sequence change is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;M;.;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	.;D;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;.;.;.
Sift4G	Uncertain	0.0020	.;D;.;.;.
Polyphen		1.0	D;D;.;D;D
Vest4		0.95
MutPred		0.93		Loss of MoRF binding (P = 0.0258);Loss of MoRF binding (P = 0.0258);.;Loss of MoRF binding (P = 0.0258);Loss of MoRF binding (P = 0.0258);
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.89
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs397514673; hg19: chr1-160011799; COSMIC: COSV100927976; COSMIC: COSV100927976;