NM_002241.5:c.500C>T

Variant names:

• chr1-160042033-G-A
• rs137853070
• NM_002241.5:c.500C>T
• KCNJ10 p.Ala167Val

Variant summary

Our verdict is Pathogenic.

+13 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPP3_ModeratePP5_Strong

The NM_002241.5(KCNJ10):c.500C>T (p.Ala167Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000173 (AC=27) in the gnomAD database across 1,560,654 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.09). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002999430: Experimental studies have shown that this missense change affects KCNJ10 function (PMID:20678478, 20807765, 21088294, 24561201)." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.A167= (synonymous): Likely_benign (ClinVar VariationId 129315, 2 stars); p.A167T: Uncertain_significance (ClinVar VariationId 4697701, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Seizures, sensorineural deafness, ataxia, impaired intellectual development, and electrolyte imbalance (SESAMES); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Predictors: REVEL: 0.83: Pathogenic
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.09
• Publications: 21 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
• paroxysmal dyskinesia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• Pendred syndrome

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 13 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV002999430: Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 20678478, 20807765, 21088294, 24561201).; SCV002499018: Published functional studies demonstrate a damaging effect resulting in a partial loss of KCNJ10 function (PMID: 20678478, 26867573);
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 6 pathogenic, 0 benign (OR vs. background: 65.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002241.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNJ10 NM_002241.5	MANE Select	c.500C>T p.Ala167Val	missense	Exon 2 of 2	Prot: NP_002232.2

KCNJ10 NM_002241.5

MANE Select

HGVSc / HGVSpc.500C>Tp.Ala167Val

Exon rankExon 2 of 2

missense

Prot: NP_002232.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNJ10 ENST00000644903.1	MANE Select	c.500C>T p.Ala167Val	missense	Exon 2 of 2	Prot: ENSP00000495557
	KCNJ10 ENST00000638728.2	TSL:5	c.500C>T p.Ala167Val	missense	Exon 3 of 3	Prot: ENSP00000492619
	KCNJ10 ENST00000638868.1	TSL:5	c.500C>T p.Ala167Val	missense	Exon 3 of 3	Prot: ENSP00000491250

KCNJ10 ENST00000644903.1

MANE Select

HGVSc / HGVSpc.500C>Tp.Ala167Val

Exon rankExon 2 of 2

missense

Prot: ENSP00000495557

KCNJ10 ENST00000638728.2

TSL:5

HGVSc / HGVSpc.500C>Tp.Ala167Val

Exon rankExon 3 of 3

missense

Prot: ENSP00000492619

KCNJ10 ENST00000638868.1

TSL:5

HGVSc / HGVSpc.500C>Tp.Ala167Val

Exon rankExon 3 of 3

missense

Prot: ENSP00000491250

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152208	Cov:32
GnomAD2 exomes	AF: 0.00000958	AC:2	Hom:	AN:208856	Cov:
GnomAD4 exome	AF: 0.0000185	AC:26	Hom:0	AN:1408446	Cov:32
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152208	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:19142	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28840
SCHEMA(Schizophrenia)	0.0000262	2	76398	0.00000776	1	128814

Showing 2 cohortsAllele count / allele number. *AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	EAST syndrome (3)
1	-	-	not provided (1)
1	-	-	Pendred syndrome;C2748572:EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.52	D
Mutation Taster	N/A	28/72	disease causing (ClinVar)
MutationAssessor	Uncertain	2.0	M
PhyloP100	Pathogenic	8.1
popEVE	Benign	-3.7
PrimateAI	Pathogenic	0.84	D
PromoterAI	N/A	-0.0040	Neutral
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.83
Sift	Benign	0.24	T
Sift4G	Benign	0.12	T
Varity_R	N/A	0.44
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs137853070;

hg19: chr1-160011823;

COSMIC: COSV100927988;

COSMIC: COSV100927988;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar