chr21-34449463-T-A

Variant names:

• chr21-34449463-T-A
• rs147187721
• NM_000219.6:c.172A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_000219.6(KCNE1):​c.172A>T​(p.Thr58Ser) variant causes a missense change. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T58N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449462-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372392.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.172A>T	p.Thr58Ser	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.172A>T	p.Thr58Ser	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.0	.;.;T;.;.;.;.;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M
PhyloP100		4.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N;.;.;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D
Vest4		0.35
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.18
gMVP		0.83
Mutation Taster		=62/38	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: rs147187721; hg19: chr21-35821761;