rs77442996

chr21-34449310-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000219.6(KCNE1):c.325G>A(p.Val109Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000066 in 1,378,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V109V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3 O:1
• Conservation: PhyloP100: -0.483

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060816973).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000602 (75/1245262) while in subpopulation AFR AF= 0.000639 (19/29752). AF 95% confidence interval is 0.000418. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 18. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.325G>A	p.Val109Ile	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.325G>A	p.Val109Ile	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes AF: 0.000120 AC: 16 AN: 133038 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.000380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000769

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000166

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251204 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135850

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 75 AN: 1245262 Hom.: 0 Cov.: 18 AF XY: 0.0000604 AC XY: 38 AN XY: 629076

Gnomad4 AFR exome AF: 0.000639

Gnomad4 AMR exome AF: 0.0000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.0000376

GnomAD4 genome AF: 0.000120 AC: 16 AN: 133152 Hom.: 0 Cov.: 17 AF XY: 0.000155 AC XY: 10 AN XY: 64378

Gnomad4 AFR AF: 0.000379

Gnomad4 AMR AF: 0.0000768

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000166

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000955 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in 5 papers in HGMD but comments suggest not pathogenic. 32 mammals have an Ile at this position. The variant is classified in ClinVar with 1 star as VUS by CSER_CC_NCGL and Royal Brompton & Harefield NHS Foundation Trust. The variant is present at 0.07% in gnomAD (18 African chrs). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2023	Variant summary: KCNE1 c.325G>A (p.Val109Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251204 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.325G>A, has been reported in the literature in individuals affected with features of Long QT Syndrome (LQTS/Arrhythmia) without strong evidence for causality, including lack of segregation in an index patient and his asymptomatic father who both carry the variant (example, Schulze-Bahr_2001, Ghouse_2015, Ohno_2007, Mahdieh_2020). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function with conflicting results (Dvir_2014; Schulze-Bahr_2001). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LB, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2023	Reported in association with LQTS (Schulze-Bahr et al., 2001); however, this variant has also been reported in control populations and in at least one individual with a normal QT interval (Ackerman et al., 2003; Ghouse et al., 2015); Two functional studies have conflicting results regarding the effect of this variant on channel function (Schulze-Bahr et al., 2001; Dvir et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 22378279, 25637381, 26159999, 14661677, 11692163, 34426522, 31043699, 32470535, 28988457, 30461122, 31941373, 25037568) -
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:11692163;PMID:14661677;PMID:22378279). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Long QT syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Mar 20, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2020

This alteration is classified as likely 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	0.067
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	0.10
Dann	Benign	0.28
DEOGEN2	Benign	0.40	T;T;T;T;T;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0044	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-1.1	N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.28	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T;.;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;B
Vest4		0.25
MVP		0.43
MPC		0.062
ClinPred		0.010	T
GERP RS		-4.6
Varity_R		0.019
gMVP		0.33

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: rs77442996; hg19: chr21-35821608;