Variant 21-34449397-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_000219.6(KCNE1):c.238G>C(p.Val80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,459,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V80I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 18)

Exomes 𝑓: 0.000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.34

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000219.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-34449397-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.24568343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.238G>C	p.Val80Leu	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.238G>C	p.Val80Leu	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143684

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000231

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251434

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1459530

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000696

AC:

AN:

143684

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

69632

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000231

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;T;T;T;T;T;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.77

.;.;T;.;.;.;.;.

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.079

MutationAssessor

Uncertain

2.7

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

Uncertain

0.51

PROVEAN

Benign

0.29

N;.;.;N;N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.42

T;.;.;T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T;T;T;T

Polyphen

0.095

B;B;B;B;B;B;B;B

Vest4

0.25

MutPred

0.35

Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);Gain of catalytic residue at V80 (P = 0.0721);

MVP

0.84

MPC

0.076

ClinPred

0.074

GERP RS

3.3

Varity_R

0.054

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over