rs17173509

Positions:

• chr21-34449480-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000219.6(KCNE1):​c.155G>C​(p.Gly52Ala) variant causes a missense change. 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G52R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 16)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.69

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 Likely_pathogenic. Variant got 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449481-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.155G>C	p.Gly52Ala	missense_variant	4/4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.155G>C	p.Gly52Ala	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 16

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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:14661677). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;.;T;.;.;.;.;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N;.;.;N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.21	T;.;.;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;D;D;D;D;D
Vest4		0.59
MutPred		0.35		Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);Gain of catalytic residue at G52 (P = 0.0634);
MVP		0.94
MPC		0.31
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.78

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: rs17173509; hg19: chr21-35821778;