rs772037564

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000238.4(KCNH2):c.697G>T(p.Ala233Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,457,400 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000061 ( 2 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.971

Variant links:

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.103696465).

BP6

Variant 7-150958278-C-A is Benign according to our data. Variant chr7-150958278-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 527096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 9 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.697G>T	p.Ala233Ser	missense_variant	4/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.697G>T	p.Ala233Ser	missense_variant	4/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000532957.5 linkuse as main transcript	n.920G>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.1530G>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

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:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000228

AC:

AN:

78984

Hom.:

AF XY:

0.000285

AC XY:

AN XY:

45542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000613

AC:

AN:

1305430

Hom.:

Cov.:

AF XY:

0.0000885

AC XY:

AN XY:

643832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000377

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00100

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.61e-7

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74302

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:

0.00165

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.000101

AC:

Asia WGS

AF:

0.000300

AC:

AN:

3350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 22, 2017

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.10

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

0.84

N;N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.70

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.18

T;.

Sift4G

Benign

0.42

T;T

Polyphen

0.23

B;.

Vest4

0.14

MutPred

0.16

Gain of phosphorylation at A233 (P = 0.0023);.;

MVP

0.54

MPC

0.93

ClinPred

0.020

GERP RS

2.6

Varity_R

0.079

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over