rs771981567

Variant names:

• chr21-34449603-G-A
• rs771981567
• NM_000219.6:c.32C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34449603-G-A
• chr21-34449603-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000219.6(KCNE1):​c.32C>T​(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain_significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 2.09
• Publications: 1 publications found

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]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24899825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.32C>T	p.Pro11Leu	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.32C>T	p.Pro11Leu	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251280 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: AS_VQSR AF: 0.00000245 AC: 2 AN: 817696 Hom.: 0 Cov.: 11 AF XY: 0.00000477 AC XY: 2 AN XY: 419044

African (AFR) AF: 0.00 AC: 0 AN: 19688

American (AMR) AF: 0.00 AC: 0 AN: 36828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18794

East Asian (EAS) AF: 0.00 AC: 0 AN: 31398

South Asian (SAS) AF: 0.0000314 AC: 2 AN: 63688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 564016

Other (OTH) AF: 0.00 AC: 0 AN: 37880

GnomAD4 genome Cov.: 13

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Long QT syndrome 5 Other:1

-

Roden Lab, Vanderbilt University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	16
DANN	Benign	0.20
DEOGEN2	Uncertain	0.45	T;T;T;T;T;T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	.;.;T;.;.;.;.;.
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	1.9	M;M;M;M;M;M;M;M
PhyloP100		2.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.53	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.14	T;.;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.054	B;B;B;B;B;B;B;B
Vest4		0.069
MutPred		0.44		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.91
MPC		0.085
ClinPred		0.094	T
GERP RS		3.9
Varity_R		0.073
gMVP		0.55
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs771981567; hg19: chr21-35821901; COSMIC: COSV61606689;