rs17173510

chr21-34449551-C-Tchr21-34449551-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000219.6(KCNE1):c.84G>A(p.Ser28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 967,632 control chromosomes in the GnomAD database, including 3,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (156 hom., cov: 12)
  • Exomes 𝑓: 0.012 (3714 hom.)
• Consequence: KCNE1 NM_000219.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -6.50

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-34449551-C-T is Benign according to our data. Variant chr21-34449551-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-34449551-C-T is described in Lovd as [Benign]. Variant chr21-34449551-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00652 (527/80802) while in subpopulation AMR AF= 0.0122 (109/8918). AF 95% confidence interval is 0.0104. There are 156 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 157 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.84G>A	p.Ser28=	synonymous_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.84G>A	p.Ser28=	synonymous_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 529 AN: 80758 Hom.: 157 Cov.: 12

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0105

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00238

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.00912

GnomAD3 exomes AF: 0.00362 AC: 909 AN: 251306 Hom.: 1 AF XY: 0.00355 AC XY: 482 AN XY: 135858

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.0120 AC: 10604 AN: 886830 Hom.: 3714 Cov.: 21 AF XY: 0.0115 AC XY: 5110 AN XY: 442666

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00847

Gnomad4 ASJ exome AF: 0.000126

Gnomad4 EAS exome AF: 0.000481

Gnomad4 SAS exome AF: 0.000319

Gnomad4 FIN exome AF: 0.00406

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.00941

GnomAD4 genome AF: 0.00652 AC: 527 AN: 80802 Hom.: 156 Cov.: 12 AF XY: 0.00591 AC XY: 233 AN XY: 39418

Gnomad4 AFR AF: 0.00153

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00238

Gnomad4 NFE AF: 0.00938

Gnomad4 OTH AF: 0.00907

Alfa AF: 0.00501 Hom.: 23

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2016	Variant summary: The KCNE1 c.84G>A (p.Ser28Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. This variant was found in 438/120954 control chromosomes at a frequency of 0.0036212, which is approximately 362 times the estimated maximal expected allele frequency of a pathogenic KCNE1 variant (0.00001), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign and multiple publications have classified the variant as "normal/polymorphism". Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	ENSG00000276289: BP4, BP7; KCNE1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser28Ser in Exon 03 of KCNE1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.6% (40/7020) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17173510). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -
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	-	- -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 17, 2022

- -

Long QT syndrome 5 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jervell and Lange-Nielsen syndrome 2 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2016

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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.010
Dann	Benign	0.62

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: rs17173510; hg19: chr21-35821849;