rs1805127

chr21-34449523-T-Cchr21-34449523-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000219.6(KCNE1):c.112A>G(p.Ser38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 74,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S38D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00069 (289 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: -1.04

Genes affected

KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5166795E-5).
• BP6: Variant 21-34449523-T-C is Benign according to our data. Variant chr21-34449523-T-C is described in ClinVar as [Benign]. Clinvar id is 132651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-34449523-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 52150 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.112A>G	p.Ser38Gly	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.112A>G	p.Ser38Gly	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes AF: 0.000203 AC: 15 AN: 74030 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000618

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000948

Gnomad FIN AF: 0.000160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000224

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.643 AC: 161537 AN: 251288 Hom.: 52150 AF XY: 0.641 AC XY: 87103 AN XY: 135834

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.699

Gnomad EAS exome AF: 0.711

Gnomad SAS exome AF: 0.654

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.639

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000692 AC: 584 AN: 843966 Hom.: 289 Cov.: 23 AF XY: 0.000727 AC XY: 305 AN XY: 419698

Gnomad4 AFR exome AF: 0.00208

Gnomad4 AMR exome AF: 0.000629

Gnomad4 ASJ exome AF: 0.000872

Gnomad4 EAS exome AF: 0.00619

Gnomad4 SAS exome AF: 0.000369

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.000479

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000203 AC: 15 AN: 74064 Hom.: 0 Cov.: 12 AF XY: 0.000193 AC XY: 7 AN XY: 36188

Gnomad4 AFR AF: 0.000179

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000618

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000951

Gnomad4 FIN AF: 0.000160

Gnomad4 NFE AF: 0.000225

Gnomad4 OTH AF: 0.00

Alfa AF: 0.635 Hom.: 65656

TwinsUK AF: 0.641 AC: 2375

ALSPAC AF: 0.636 AC: 2453

ESP6500AA AF: 0.711 AC: 3132

ESP6500EA AF: 0.637 AC: 5477

ExAC AF: 0.647 AC: 78583

Asia WGS AF: 0.710 AC: 2465 AN: 3478

EpiCase AF: 0.632

EpiControl AF: 0.630

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser38Gly in Exon 03 of KCNE1: This variant is not expected to have clinical sign ificance because it has been identified in 37.2% (2612/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1805127). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2013	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, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Long QT syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jervell and Lange-Nielsen syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:18426444;PMID:17597962;PMID:12402336;PMID:14760488;PMID:16487223;PMID:17210839;PMID:9445165;PMID:7828904;PMID:15599693;PMID:17161064;PMID:14661677). -

Noise induced hearing loss Benign:1

Benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Congenital long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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	0.056
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	2.4
Dann	Benign	0.89
DEOGEN2	Benign	0.40	T;T;T;T;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0040	N
MetaRNN	Benign	0.000035	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.43	N;.;.;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.40	T;.;.;T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;B
Vest4		0.019
MPC		0.068
ClinPred		0.015	T
GERP RS		0.18
Varity_R		0.038
gMVP		0.39

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: rs1805127; hg19: chr21-35821821; COSMIC: COSV61606368;