17-70176185-C-T

Position:

chr17-70176185-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000891.3(KCNJ2):c.1146C>T(p.Leu382=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,708 control chromosomes in the GnomAD database, including 12,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1313 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10940 hom. )

Consequence

KCNJ2
NM_000891.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) 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, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

KCNJ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 17-70176185-C-T is Benign according to our data. Variant chr17-70176185-C-T is described in ClinVar as [Benign]. Clinvar id is 137988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70176185-C-T is described in Lovd as [Benign]. Variant chr17-70176185-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.32 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3 linkuse as main transcript	c.1146C>T	p.Leu382=	synonymous_variant	2/2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 linkuse as main transcript	c.1146C>T	p.Leu382=	synonymous_variant	2/2	1	NM_000891.3	ENSP00000243457	P1
KCNJ2	ENST00000535240.1 linkuse as main transcript	c.1146C>T	p.Leu382=	synonymous_variant	2/2	1		ENSP00000441848	P1

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19641

AN:

151876

Hom.:

1312

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.140

GnomAD3 exomes

AF:

0.136

AC:

34181

AN:

250672

Hom.:

2536

AF XY:

0.135

AC XY:

18326

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.230

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.107

Gnomad SAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.0903

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.121

AC:

176347

AN:

1461714

Hom.:

10940

Cov.:

AF XY:

0.121

AC XY:

87878

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.224

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.0992

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.0932

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.124

GnomAD4 genome

AF:

0.129

AC:

19659

AN:

151994

Hom.:

1313

Cov.:

AF XY:

0.130

AC XY:

9641

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.139

Gnomad4 AMR

AF:

0.187

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.165

Gnomad4 FIN

AF:

0.0924

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.138

Alfa

AF:

0.128

Hom.:

966

Bravo

AF:

0.138

Asia WGS

AF:

0.124

AC:

432

AN:

3478

EpiCase

AF:

0.113

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2011	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+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Andersen Tawil syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atrial fibrillation, familial, 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 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. -

Short QT syndrome type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.9

DANN

Benign

0.72

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