21-34449472-C-T

Position:

chr21-34449472-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_000219.6(KCNE1):c.163G>A(p.Gly55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,202,928 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000048 ( 0 hom., cov: 16)

Exomes 𝑓: 0.000063 ( 4 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1O:2

Conservation

PhyloP100: 3.10

Variant links:

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]

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000219.6

BP4

Computational evidence support a benign effect (MetaRNN=0.30607957).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000628 (69/1099208) while in subpopulation SAS AF= 0.000432 (33/76392). AF 95% confidence interval is 0.000315. There are 4 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.163G>A	p.Gly55Ser	missense_variant	4/4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.163G>A	p.Gly55Ser	missense_variant	4/4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.0000482

AC:

AN:

103632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000335

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000208

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251428

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000628

AC:

AN:

1099208

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

557970

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000483

Gnomad4 ASJ exome

AF:

0.0000430

Gnomad4 EAS exome

AF:

0.0000830

Gnomad4 SAS exome

AF:

0.000432

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000328

Gnomad4 OTH exome

AF:

0.0000208

GnomAD4 genome

AF:

0.0000482

AC:

AN:

103720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

50074

show subpopulations

Gnomad4 AFR

AF:

0.000113

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000336

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000208

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000820

Hom.:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2020	Reported in one individual referred for LQTS genetic testing (Kapplinger et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000549147.3, SCV000198416.4; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24710009, 19716085, 31941373, 28988457) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 12, 2018	Variant KCNE1 p.Gly55Ser (c.163G>A) exon 4 (NM_000219.5, hg19 chr21-35821770-C-T) SCICD classification variant of uncertain significance, probably benign We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: too high MAF. (rs199473644, ExAC 0.07%)" 0.05198% MAF in South Asians -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2014

Variant classified as Uncertain Significance - Favor Benign. The Gly55Ser varian t in KCNE1 has not been previously reported in any individuals with hearing loss and was absent from large population studies. However, this variant has been re ported in one individual with long QT syndrome (Kapplinger 2009). The glycine (G ly) residue at position 55 is not conserved across several species including two mammals (hamster and mole) having serine (Ser) at this position, suggesting tha t the variant may be tolerated. However, this information is not sufficient to r ule out pathogenicity. In summary, the clinical significance of this variant can not be determined with certainty; however based upon the conservation data, we w ould lean towards a more likely benign role. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 55 of the KCNE1 protein (p.Gly55Ser). This variant is present in population databases (rs199473644, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of LQTS (PMID: 19716085, 31941373). ClinVar contains an entry for this variant (Variation ID: 132657). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17545244). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

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. -

Long QT syndrome 5

Other:1

not provided, no classification provided

in vitro

Roden Lab, Vanderbilt University Medical Center

- -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;D;D;D;D;D;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

.;.;T;.;.;.;.;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.3

N;.;.;N;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.28

T;.;.;T;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T;T;T

Polyphen

0.98

D;D;D;D;D;D;D;D

Vest4

0.43

MutPred

0.34

Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);Gain of catalytic residue at G55 (P = 0.1848);

MVP

0.93

MPC

0.29

ClinPred

0.41

GERP RS

5.2

Varity_R

0.12

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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