7-150958122-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000238.4(KCNH2):c.853G>T(p.Ala285Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A285V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
short QT syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.31133482).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	NM_000238.4	MANE Select	c.853G>T	p.Ala285Ser	missense	Exon 4 of 15	NP_000229.1
KCNH2	NM_001406753.1		c.565G>T	p.Ala189Ser	missense	Exon 2 of 13	NP_001393682.1
KCNH2	NM_172056.3		c.853G>T	p.Ala285Ser	missense	Exon 4 of 9	NP_742053.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.853G>T	p.Ala285Ser	missense	Exon 4 of 15	ENSP00000262186.5
KCNH2	ENST00000713710.1		c.853G>T	p.Ala285Ser	missense	Exon 4 of 15	ENSP00000519013.1
KCNH2	ENST00000713701.1		c.553G>T	p.Ala185Ser	missense	Exon 3 of 14	ENSP00000519004.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1149226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

551200

African (AFR)

AF:

0.00

AC:

AN:

23164

American (AMR)

AF:

0.00

AC:

AN:

9478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15642

East Asian (EAS)

AF:

0.00

AC:

AN:

26406

South Asian (SAS)

AF:

0.00

AC:

AN:

37072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

961344

Other (OTH)

AF:

0.00

AC:

AN:

46926

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostArm

Benign

0.0053

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.50

Sift

Uncertain

0.029

Sift4G

Benign

0.57

Polyphen

0.61

Vest4

0.27

MutPred

0.32

Gain of phosphorylation at A285 (P = 0.0187)

MVP

0.92

MPC

1.0

ClinPred

0.25

GERP RS

3.8

Varity_R

0.20

gMVP

0.56

Mutation Taster

=87/13

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