rs28933384

Positions:

• chr21-34449615-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP5

The NM_000219.6(KCNE1):​c.20C>T​(p.Thr7Ile) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 13)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.28

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 21-34449615-G-A is Pathogenic according to our data. Variant chr21-34449615-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13476.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-34449615-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.20C>T	p.Thr7Ile	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.20C>T	p.Thr7Ile	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 11

GnomAD4 genome Cov.: 13

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Jervell and Lange-Nielsen syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1997

- -

Congenital long QT syndrome 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:9354783). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;D;D;D;D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
MutationTaster	Benign	0.94	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;.;.;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.57
MutPred		0.32		Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);
MVP		0.96
MPC		0.45
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.89

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: rs28933384; hg19: chr21-35821913;