rs137853072

Variant names:

• chr1-160042304-C-G
• rs137853072
• NM_002241.5:c.229G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_002241.5(KCNJ10):​c.229G>C​(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.29
• Publications: 24 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002241.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.968
• PP5: Variant 1-160042304-C-G is Pathogenic according to our data. Variant chr1-160042304-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7468.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ10	NM_002241.5	c.229G>C	p.Gly77Arg	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.229G>C	p.Gly77Arg	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

EAST syndrome Pathogenic:2

Nov 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the KCNJ10 protein (p.Gly77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SeSAME syndrome (PMID: 19420365; Invitae). ClinVar contains an entry for this variant (Variation ID: 7468). 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 not expected to disrupt KCNJ10 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 19420365, 20807765, 21088294). This variant disrupts the p.Gly77 amino acid residue in KCNJ10. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ10-related conditions (PMID: 31069529), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	.;.;D;D;.;D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;.;.;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	.;.;M;M;.;M;M
PhyloP100		2.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.5	.;.;.;N;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.027	.;.;.;D;.;.;.
Sift4G	Uncertain	0.030	.;.;.;D;.;.;.
Polyphen		0.99	.;.;D;D;.;D;D
Vest4		0.89
MutPred		0.95		Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);.;Gain of methylation at G77 (P = 0.0159);Gain of methylation at G77 (P = 0.0159);
MVP		0.99
MPC		1.5
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		0.024	Neutral
Varity_R		0.85
gMVP		0.99
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs137853072; hg19: chr1-160012094;