Genetic Variant KCNE1:p.Ser38Arg (chr21-34449523-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_000219.6(KCNE1):c.112A>C(p.Ser38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. S38I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 12)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.04

Publications

150 publications found

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 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

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.10619265).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000219.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNE1	NM_000219.6	MANE Select	c.112A>C	p.Ser38Arg	missense	Exon 4 of 4	NP_000210.2
KCNE1	NM_001127668.4		c.112A>C	p.Ser38Arg	missense	Exon 3 of 3	NP_001121140.1
KCNE1	NM_001127669.4		c.112A>C	p.Ser38Arg	missense	Exon 3 of 3	NP_001121141.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNE1	ENST00000399286.3	TSL:1 MANE Select	c.112A>C	p.Ser38Arg	missense	Exon 4 of 4	ENSP00000382226.2
KCNE1	ENST00000399289.7	TSL:1	c.112A>C	p.Ser38Arg	missense	Exon 3 of 3	ENSP00000382228.3
KCNE1	ENST00000416357.6	TSL:1	c.112A>C	p.Ser38Arg	missense	Exon 2 of 2	ENSP00000416258.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

844044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

419742

African (AFR)

AF:

0.00

AC:

AN:

16354

American (AMR)

AF:

0.00

AC:

AN:

28616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13764

East Asian (EAS)

AF:

0.00

AC:

AN:

18432

South Asian (SAS)

AF:

0.00

AC:

AN:

48818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3418

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

645088

Other (OTH)

AF:

0.00

AC:

AN:

34242

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0042

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.2

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.56

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.17

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.34

PhyloP100

-1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.32

Sift

Benign

0.24

Sift4G

Benign

0.51

Polyphen

0.0030

Vest4

0.058

MutPred

0.20

Gain of solvent accessibility (P = 0.0155)

MVP

0.57

MPC

0.093

ClinPred

0.039

GERP RS

0.18

Varity_R

0.071

gMVP

0.46

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over