rs173135

chr17-70176185-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.32

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]

ACMG classification

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	UniProt
KCNJ2	NM_000891.3	c.1146C>T	p.Leu382=	synonymous_variant	2/2	ENST00000243457.4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19641 AN: 151876 Hom.: 1312 Cov.: 32

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

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.: 33 AF XY: 0.121 AC XY: 87878 AN XY: 727164

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.: 32 AF XY: 0.130 AC XY: 9641 AN XY: 74300

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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

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. -

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

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. -

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

Other links and lift over

dbSNP: rs173135; hg19: chr17-68172326; COSMIC: COSV54660636;