rs145947380

Variant names:

• chr1-160042003-T-C
• rs145947380
• NM_002241.5:c.530A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS1

The NM_002241.5(KCNJ10):​c.530A>G​(p.Glu177Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,573,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: KCNJ10 NM_002241.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 5.09
• Publications: 4 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_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.032052487).
• BP6: Variant 1-160042003-T-C is Benign according to our data. Variant chr1-160042003-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195165.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000407 (62/152210) while in subpopulation NFE AF = 0.000632 (43/68034). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	NM_002241.5	MANE Select	c.530A>G	p.Glu177Gly	missense	Exon 2 of 2	NP_002232.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	ENST00000644903.1	MANE Select	c.530A>G	p.Glu177Gly	missense	Exon 2 of 2	ENSP00000495557.1
	KCNJ10	ENST00000638728.1	TSL:5	c.530A>G	p.Glu177Gly	missense	Exon 3 of 3	ENSP00000492619.1
	KCNJ10	ENST00000638868.1	TSL:5	c.530A>G	p.Glu177Gly	missense	Exon 3 of 3	ENSP00000491250.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000476 AC: 105 AN: 220792 AF XY: 0.000494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00708

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000363

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.000378

GnomAD4 exome AF: 0.000364 AC: 518 AN: 1421166 Hom.: 0 Cov.: 32 AF XY: 0.000372 AC XY: 261 AN XY: 701480

African (AFR) AF: 0.0000307 AC: 1 AN: 32544

American (AMR) AF: 0.0000481 AC: 2 AN: 41606

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 136 AN: 23082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 78688

European-Finnish (FIN) AF: 0.000329 AC: 17 AN: 51630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.000310 AC: 338 AN: 1090232

Other (OTH) AF: 0.000410 AC: 24 AN: 58498

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000718 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000454 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jul 14, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a pathogenic SLC26A4 variant in a patient with profound congenital sensorineural hearing loss in published literature (PMID: 40121402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 40121402)

Nov 10, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EAST syndrome Uncertain:1 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNJ10 NM_002241 exon 2 p.Glu177Gly (c.530A>G): This variant has not been reported in the literature but is present in 0.7% (50/6682) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs145947380). This variant is present in ClinVar (Variation ID: 195165). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Inborn genetic diseases Benign:1

Feb 29, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

KCNJ10-related disorder Benign:1

Feb 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.040	D
Polyphen		0.55	P
Vest4		0.14
MVP		0.49
MPC		0.74
ClinPred		0.16	T
GERP RS		5.4
PromoterAI		-0.023	Neutral
Varity_R		0.50
gMVP		0.81
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145947380; hg19: chr1-160011793; COSMIC: COSV105294512; COSMIC: COSV105294512;