1-160041721-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_002241.5(KCNJ10):c.812G>A(p.Arg271His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,898 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 8 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.12

Publications

18 publications found

Variant links:

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: G2P, Orphanet, Ambry Genetics, 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

KCNJ10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

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=0.006831944).

BP6

Variant 1-160041721-C-T is Benign according to our data. Variant chr1-160041721-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129318.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00126 (192/152090) while in subpopulation EAS AF = 0.0159 (82/5144). AF 95% confidence interval is 0.0132. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ10	NM_002241.5	MANE Select	c.812G>A	p.Arg271His	missense	Exon 2 of 2	NP_002232.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNJ10	ENST00000644903.1	MANE Select	c.812G>A	p.Arg271His	missense	Exon 2 of 2	ENSP00000495557.1	P78508
KCNJ10	ENST00000638728.1	TSL:5	c.812G>A	p.Arg271His	missense	Exon 3 of 3	ENSP00000492619.1	P78508
KCNJ10	ENST00000638868.1	TSL:5	c.812G>A	p.Arg271His	missense	Exon 3 of 3	ENSP00000491250.1	P78508

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0159

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00756

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00215

AC:

541

AN:

251398

AF XY:

0.00198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.00827

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00101

AC:

1482

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000974

AC XY:

708

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0208

AC:

827

AN:

39700

South Asian (SAS)

AF:

0.000301

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00805

AC:

430

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000121

AC:

135

AN:

1111934

Other (OTH)

AF:

0.000960

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152090

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

118

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41484

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0159

AC:

AN:

5144

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00756

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000750

Hom.:

Bravo

AF:

0.000880

ExAC

AF:

0.00189

AC:

230

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

EAST syndrome (2)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 4 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Benign

0.040

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0068

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.94

PhyloP100

2.1

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.22

REVEL

Uncertain

0.35

Sift

Benign

0.073

Sift4G

Benign

0.13

Polyphen

0.11

Vest4

0.17

MVP

0.75

MPC

0.67

ClinPred

0.031

GERP RS

5.4

PromoterAI

-0.0056

Neutral

(source)

Varity_R

0.13

gMVP

0.29

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over