1-160042233-G-T

Position:

chr1-160042233-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_002241.5(KCNJ10):c.300C>A(p.Asp100Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D100D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

KCNJ10
NM_002241.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -6.36

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 links:

KCNJ10 (HGNC:):

KCNJ10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05019182).

BP6

Variant 1-160042233-G-T is Benign according to our data. Variant chr1-160042233-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435553.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr1-160042233-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ10	NM_002241.5 linkuse as main transcript	c.300C>A	p.Asp100Glu	missense_variant	2/2	ENST00000644903.1	NP_002232.2	P78508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ10	ENST00000644903.1 linkuse as main transcript	c.300C>A	p.Asp100Glu	missense_variant	2/2		NM_002241.5	ENSP00000495557.1		P78508

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000164

AC:

AN:

250344

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000288

AC:

421

AN:

1461666

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000357

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000237

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 03, 2015

- -

EAST syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 08, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

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. -

EAST syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.061

DANN

Benign

0.60

DEOGEN2

Benign

0.40

.;.;T;T;.;T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.45

T;T;.;.;T;.;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.050

T;T;T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.85

.;.;L;L;.;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.36

.;.;.;N;.;.;.

REVEL

Benign

0.25

Sift

Benign

1.0

.;.;.;T;.;.;.

Sift4G

Benign

0.99

.;.;.;T;.;.;.

Polyphen

0.0010

.;.;B;B;.;B;B

Vest4

0.021

MutPred

0.38

Gain of glycosylation at P102 (P = 0.0789);Gain of glycosylation at P102 (P = 0.0789);Gain of glycosylation at P102 (P = 0.0789);Gain of glycosylation at P102 (P = 0.0789);.;Gain of glycosylation at P102 (P = 0.0789);Gain of glycosylation at P102 (P = 0.0789);

MVP

0.28

MPC

0.49

ClinPred

0.034

GERP RS

-9.9

Varity_R

0.038

gMVP

0.84

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over