rs137853069

Variant names:

• chr1-160042042-G-A
• rs137853069
• NM_002241.5:c.491C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_002241.5(KCNJ10):​c.491C>T​(p.Thr164Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.70
• Publications: 20 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 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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.
• PP5: Variant 1-160042042-G-A is Pathogenic according to our data. Variant chr1-160042042-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7465.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ10	NM_002241.5	c.491C>T	p.Thr164Ile	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.491C>T	p.Thr164Ile	missense_variant	Exon 2 of 2		NM_002241.5	ENSP00000495557.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00210 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

EAST syndrome Pathogenic:1

Nov 12, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;.;T;.;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.70	N;N;.;N;N
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.65	.;N;.;.;.
REVEL	Pathogenic	0.67
Sift	Benign	0.32	.;T;.;.;.
Sift4G	Benign	0.53	.;T;.;.;.
Polyphen		1.0	D;D;.;D;D
Vest4		0.19
MutPred		0.51		Loss of catalytic residue at T164 (P = 0.0926);Loss of catalytic residue at T164 (P = 0.0926);.;Loss of catalytic residue at T164 (P = 0.0926);Loss of catalytic residue at T164 (P = 0.0926);
MVP		0.89
MPC		1.5
ClinPred		0.87	D
GERP RS		5.3
PromoterAI		-0.027	Neutral
Varity_R		0.47
gMVP		0.86
Mutation Taster		=16/84	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: rs137853069; hg19: chr1-160011832;