chr21-34449496-C-A

Variant names:

• chr21-34449496-C-A
• rs199473353
• NM_000219.6:c.139G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000219.6(KCNE1):​c.139G>T​(p.Val47Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 14)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 1.43

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 Uncertain_significance. Variant got 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.139G>T	p.Val47Phe	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.139G>T	p.Val47Phe	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 14

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

Long QT syndrome 5 Other:1

-

Roden Lab, Vanderbilt University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Congenital long QT syndrome Other:1

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10400998). 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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D;D;D;D;D;D
Eigen	Benign	0.065
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	.;.;T;.;.;.;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D;.;.;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		0.77	P;P;P;P;P;P;P;P
Vest4		0.77
MutPred		0.26		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.86
MPC		0.41
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.28
gMVP		0.83

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: rs199473353; hg19: chr21-35821794;