rs199473393

Positions:

• chr21-34449433-A-T

Variant summary

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

The ENST00000399286.3(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S68A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 ENST00000399286.3 missense
• Clinical Significance: not provided no classification provided O:2
• 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, 17 uncertain in ENST00000399286.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.202T>A	p.Ser68Thr	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.202T>A	p.Ser68Thr	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 17

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

Long QT syndrome 5 Other:1

not provided, no classification provided

in vitro

Roden Lab, Vanderbilt University Medical Center

-

- -

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
LIST_S2	Benign	0.75	.;.;T;.;.;.;.;.
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;