rs778439872

chr21-34449517-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000219.6(KCNE1):c.118G>A(p.Gly40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 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. G40G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.000027 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.677

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014184296).
• BP6: Variant 21-34449517-C-T is Benign according to our data. Variant chr21-34449517-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527042.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.118G>A	p.Gly40Ser	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.118G>A	p.Gly40Ser	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251398 Hom.: 2 AF XY: 0.000140 AC XY: 19 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00163

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000270 AC: 23 AN: 853144 Hom.: 10 Cov.: 23 AF XY: 0.0000259 AC XY: 11 AN XY: 424408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.0000277

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

Alfa AF: 0.0000555 Hom.: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 01, 2020

- -

KCNE1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2019

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	-0.42	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	0.77
Dann	Benign	0.79
DEOGEN2	Benign	0.40	T;T;T;T;T;T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.010	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	0.27	T
PROVEAN	Benign	-0.17	N;.;.;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.47	T;.;.;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B;B;B
Vest4		0.023
MutPred		0.19		Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);Gain of phosphorylation at G40 (P = 0.0595);
MVP		0.48
MPC		0.077
ClinPred		0.020	T
GERP RS		-6.5
Varity_R		0.034
gMVP		0.42

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: rs778439872; hg19: chr21-35821815;