rs199473393

Positions:

• chr21-34449433-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000219.6(KCNE1):​c.202T>A​(p.Ser68Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.00

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.202T>A	p.Ser68Thr	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.202T>A	p.Ser68Thr	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 17

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;D;D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D
Polyphen		0.94	P;P;P;P;P;P;P;P
Vest4		0.41
MutPred		0.47		Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);Loss of disorder (P = 0.0549);
MVP		0.97
MPC		0.40
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.53
gMVP		0.75

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: rs199473393; hg19: chr21-35821731;