rs199473349

chr21-34449576-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000219.6(KCNE1):c.59C>T(p.Thr20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. T20T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.628

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15690786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.59C>T	p.Thr20Ile	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.59C>T	p.Thr20Ile	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251242 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 933376 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 469214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

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 as associated with Long QT syndrome in the following publications (PMID:19322600). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	6.0
Dann	Benign	0.81
DEOGEN2	Uncertain	0.61	D;D;D;D;D;D;D;D
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.050	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.72	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.40	T;.;.;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T;T;T
Polyphen		0.068	B;B;B;B;B;B;B;B
Vest4		0.28
MutPred		0.26		Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);Loss of disorder (P = 0.0438);
MVP		0.84
MPC		0.080
ClinPred		0.065	T
GERP RS		-1.6
Varity_R		0.028
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473349; hg19: chr21-35821874;