rs34811413

Positions:

chr12-21765997-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004982.4(KCNJ8):c.1001T>C(p.Val334Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00313 in 1,613,872 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 64 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 70 hom. )

Consequence

KCNJ8
NM_004982.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

KCNJ8 (HGNC:6269): (potassium inwardly rectifying channel subfamily J member 8) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. Defects in this gene may be a cause of J-wave syndromes and sudden infant death syndrome (SIDS). [provided by RefSeq, May 2012]

KCNJ8 links:

KCNJ8 (HGNC:):

KCNJ8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ8. . Gene score misZ 3.4549 (greater than the threshold 3.09). Trascript score misZ 4.3809 (greater than threshold 3.09). GenCC has associacion of gene with hypertrichotic osteochondrodysplasia Cantu type, Brugada syndrome, Brugada syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.008663863).

BP6

Variant 12-21765997-A-G is Benign according to our data. Variant chr12-21765997-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21765997-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ8	NM_004982.4 linkuse as main transcript	c.1001T>C	p.Val334Ala	missense_variant	3/3	ENST00000240662.3	NP_004973.1	Q15842A0A024RAV6
LOC105369689	XR_007063241.1 linkuse as main transcript	n.631+5912A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ8	ENST00000240662.3 linkuse as main transcript	c.1001T>C	p.Val334Ala	missense_variant	3/3	1	NM_004982.4	ENSP00000240662.2		Q15842

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2544

AN:

151864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.00437

AC:

1099

AN:

251408

Hom.:

AF XY:

0.00302

AC XY:

410

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0603

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00171

AC:

2503

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1068

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0620

Gnomad4 AMR exome

AF:

0.00262

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.00401

GnomAD4 genome

AF:

0.0167

AC:

2544

AN:

151982

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1213

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0579

Gnomad4 AMR

AF:

0.00733

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.0143

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.0192

ESP6500AA

AF:

0.0517

AC:

228

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00513

AC:

623

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	- -

SUDDEN INFANT DEATH SYNDROME

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Aug 24, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Brugada syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.14

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.36

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.12

REVEL

Benign

0.28

Sift

Benign

0.49

Sift4G

Benign

0.51

Polyphen

0.0050

Vest4

0.39

MVP

0.90

MPC

1.5

ClinPred

0.0091

GERP RS

5.4

Varity_R

0.12

gMVP

0.74

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