chr7-150948446-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_000238.4(KCNH2):c.2690A>T(p.Lys897Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 982,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K897R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH2
NM_000238.4 missense, splice_region

Scores

Splicing: ADA: 0.09944

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.77

Publications

207 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 3 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.

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.2690A>T	p.Lys897Met	missense splice_region	Exon 11 of 15	NP_000229.1
KCNH2	NM_001406753.1		c.2402A>T	p.Lys801Met	missense splice_region	Exon 9 of 13	NP_001393682.1
KCNH2	NM_172057.3		c.1670A>T	p.Lys557Met	missense splice_region	Exon 7 of 11	NP_742054.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.2690A>T	p.Lys897Met	missense splice_region	Exon 11 of 15	ENSP00000262186.5
KCNH2	ENST00000330883.9	TSL:1	c.1670A>T	p.Lys557Met	missense splice_region	Exon 7 of 11	ENSP00000328531.4
KCNH2	ENST00000713710.1		c.2624A>T	p.Lys875Met	missense splice_region	Exon 11 of 15	ENSP00000519013.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116930

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000305

AC:

AN:

982178

Hom.:

Cov.:

AF XY:

0.00000602

AC XY:

AN XY:

498550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18114

American (AMR)

AF:

0.00

AC:

AN:

37990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17984

East Asian (EAS)

AF:

0.0000612

AC:

AN:

16334

South Asian (SAS)

AF:

0.00

AC:

AN:

74438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4336

European-Non Finnish (NFE)

AF:

0.00000269

AC:

AN:

743898

Other (OTH)

AF:

0.00

AC:

AN:

38798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

116938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56512

African (AFR)

AF:

0.00

AC:

AN:

28996

American (AMR)

AF:

0.00

AC:

AN:

11598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2948

East Asian (EAS)

AF:

0.00

AC:

AN:

3368

South Asian (SAS)

AF:

0.00

AC:

AN:

3666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57338

Other (OTH)

AF:

0.00

AC:

AN:

1646

Alfa

AF:

0.00

Hom.:

11563

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)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

CardioboostArm

Benign

0.0096

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.019

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.51

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.7

PhyloP100

2.8

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.66

Sift

Benign

0.049

Sift4G

Benign

0.13

Polyphen

0.97

Vest4

0.59

MutPred

0.26

Loss of ubiquitination at K897 (P = 0.0039)

MVP

0.88

MPC

0.32

ClinPred

0.78

GERP RS

-0.036

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.089

gMVP

0.78

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.099

dbscSNV1_RF

Benign

0.36

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over