12-21765733-G-A

Position:

chr12-21765733-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_004982.4(KCNJ8):c.1265C>T(p.Ser422Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,842 control chromosomes in the GnomAD database, including 9 homozygotes. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

KCNJ8
NM_004982.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 2.48

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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=0.0040097833).

BP6

Variant 12-21765733-G-A is Benign according to our data. Variant chr12-21765733-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 157543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-21765733-G-A is described in Lovd as [Pathogenic]. Variant chr12-21765733-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ8	NM_004982.4 linkuse as main transcript	c.1265C>T	p.Ser422Leu	missense_variant	3/3	ENST00000240662.3	NP_004973.1
LOC105369689	XR_007063241.1 linkuse as main transcript	n.631+5648G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ8	ENST00000240662.3 linkuse as main transcript	c.1265C>T	p.Ser422Leu	missense_variant	3/3	1	NM_004982.4	ENSP00000240662	P1
	ENST00000542489.1 linkuse as main transcript	n.107-623G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00183

AC:

461

AN:

251364

Hom.:

AF XY:

0.00179

AC XY:

243

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00106

AC:

1552

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

814

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.0310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000385

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152278

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.0328

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00115

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	KCNJ8: PP2, BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2020	This variant is associated with the following publications: (PMID: 23414114, 23632791, 22562657, 20558321, 22056721, 22840528, 24068186, 24667784, 19120683, 30847666) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KCNJ8-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

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

Brugada syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 19, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2017

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

0.068

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.26

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.68

M_CAP

Benign

0.019

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.62

REVEL

Benign

0.19

Sift

Benign

0.21

Sift4G

Benign

0.25

Polyphen

0.013

Vest4

0.10

MVP

0.43

MPC

0.93

ClinPred

0.012

GERP RS

4.5

Varity_R

0.069

gMVP

0.61

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