Genetic Variant KCNE1:p.Arg36Pro (chr21-34449528-C-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.107G>C(p.Arg36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36L) 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

- - O:1

Conservation

PhyloP100: -0.144

Publications

0 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=0.0936304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.107G>C	p.Arg36Pro	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.107G>C	p.Arg36Pro	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

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

AF:

0.00

AC:

AN:

846664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

420998

African (AFR)

AF:

0.00

AC:

AN:

16400

American (AMR)

AF:

0.00

AC:

AN:

28658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13804

East Asian (EAS)

AF:

0.00

AC:

AN:

18420

South Asian (SAS)

AF:

0.00

AC:

AN:

48940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3424

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

647100

Other (OTH)

AF:

0.00

AC:

AN:

34374

GnomAD4 genome

Cov.:

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

LINK: link

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

0.093

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.22

CADD

Benign

6.9

(source)

DANN

Benign

0.83

DEOGEN2

Uncertain

0.60

D;D;D;D;D;D;D;D

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.45

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

M_CAP

Benign

0.084

MetaRNN

Benign

0.094

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

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.90

L;L;L;L;L;L;L;L

PhyloP100

-0.14

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.88

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

REVEL

Uncertain

0.38

Sift

Benign

0.27

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

Sift4G

Benign

0.25

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

Polyphen

0.0

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

Vest4

0.046

MutPred

0.30

Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);Gain of glycosylation at R36 (P = 0.0043);

MVP

0.67

MPC

0.11

ClinPred

0.035

GERP RS

1.0

Varity_R

0.12

gMVP

0.56

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over