chr7-150947813-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_000238.4(KCNH2):c.2758C>T(p.Arg920Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,529,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R920Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 1.20

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

BS2

High AC in GnomAdExome4 at 19 AD gene.

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.2758C>T	p.Arg920Trp	missense	Exon 12 of 15	NP_000229.1
KCNH2	NM_001406753.1		c.2470C>T	p.Arg824Trp	missense	Exon 10 of 13	NP_001393682.1
KCNH2	NM_172057.3		c.1738C>T	p.Arg580Trp	missense	Exon 8 of 11	NP_742054.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2758C>T	p.Arg920Trp	missense	Exon 12 of 15	ENSP00000262186.5
KCNH2	ENST00000330883.9	TSL:1	c.1738C>T	p.Arg580Trp	missense	Exon 8 of 11	ENSP00000328531.4
KCNH2	ENST00000713710.1		c.2692C>T	p.Arg898Trp	missense	Exon 12 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152062

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

125518

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000160

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000138

AC:

AN:

1377030

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

678700

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31392

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24666

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35592

South Asian (SAS)

AF:

0.00

AC:

AN:

78006

European-Finnish (FIN)

AF:

0.0000282

AC:

AN:

35522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.0000140

AC:

AN:

1075192

Other (OTH)

AF:

0.0000174

AC:

AN:

57378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (2)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

not provided (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

CardioboostArm

Benign

0.0021

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

0.90

PhyloP100

1.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.69

Sift

Benign

0.17

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.33

MutPred

0.77

Loss of solvent accessibility (P = 6e-04)

MVP

0.97

MPC

0.17

ClinPred

0.42

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.087

gMVP

0.62

Mutation Taster

=1/99

disease causing

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over