1-160042032-CG-TA

Variant names:

• chr1-160042032-CG-TA
• NM_002241.5:c.500_501delinsTA
• KCNJ10 p.Ala167Val

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2

The NM_002241.5(KCNJ10):c.500_501delinsTA (p.Ala167Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.09). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: not found (cov: 32)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09
• Publications: 0 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 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars). Entries: p.A→V 1-160042033-G-A: Pathogenic (ClinVar VariationId 7466, 2 stars).
	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		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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.500_501delinsTA p.Ala167Val	missense	Exon 2 of 2	Prot: NP_002232.2

KCNJ10 NM_002241.5

MANE Select

HGVSc / HGVSpc.500_501delinsTAp.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.500_501delinsTA p.Ala167Val	missense	Exon 2 of 2	Prot: ENSP00000495557
	KCNJ10 ENST00000638728.2	TSL:5	c.500_501delinsTA p.Ala167Val	missense	Exon 3 of 3	Prot: ENSP00000492619
	KCNJ10 ENST00000638868.1	TSL:5	c.500_501delinsTA p.Ala167Val	missense	Exon 3 of 3	Prot: ENSP00000491250

KCNJ10 ENST00000644903.1

MANE Select

HGVSc / HGVSpc.500_501delinsTAp.Ala167Val

Exon rankExon 2 of 2

missense

Prot: ENSP00000495557

KCNJ10 ENST00000638728.2

TSL:5

HGVSc / HGVSpc.500_501delinsTAp.Ala167Val

Exon rankExon 3 of 3

missense

Prot: ENSP00000492619

KCNJ10 ENST00000638868.1

TSL:5

HGVSc / HGVSpc.500_501delinsTAp.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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.1

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr1-160011822;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar