rs199473034

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS2_Supporting

The NM_000238.4(KCNH2):c.3430G>A(p.Ala1144Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000569 in 1,580,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1144A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 0.347

Publications

3 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), G2P, Ambry Genetics
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
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, short QT syndrome type 1, short QT syndrome, Brugada syndrome, long QT syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.24127725).

BS2

High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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	UniProt
KCNH2	NM_000238.4	MANE Select	c.3430G>A	p.Ala1144Thr	missense	Exon 15 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.3142G>A	p.Ala1048Thr	missense	Exon 13 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172057.3		c.2410G>A	p.Ala804Thr	missense	Exon 11 of 11	NP_742054.1	Q12809-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.3430G>A	p.Ala1144Thr	missense	Exon 15 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.2410G>A	p.Ala804Thr	missense	Exon 11 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000713710.1		c.3364G>A	p.Ala1122Thr	missense	Exon 15 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD2 exomes

AF:

0.00000530

AC:

AN:

188510

AF XY:

0.00000982

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000490

AC:

AN:

1428408

Hom.:

Cov.:

AF XY:

0.00000707

AC XY:

AN XY:

707442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32850

American (AMR)

AF:

0.00

AC:

AN:

40286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25484

East Asian (EAS)

AF:

0.00

AC:

AN:

38076

South Asian (SAS)

AF:

0.00

AC:

AN:

81620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5568

European-Non Finnish (NFE)

AF:

0.00000639

AC:

AN:

1095468

Other (OTH)

AF:

0.00

AC:

AN:

59040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome (2)

Cardiovascular phenotype (1)

Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

CardioboostArm

Benign

0.000076

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.33

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.055

MutationAssessor

Benign

-0.69

PhyloP100

0.35

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.41

REVEL

Uncertain

0.53

Sift

Benign

0.53

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.44

MutPred

0.65

Gain of phosphorylation at A1144 (P = 0.045)

MVP

1.0

MPC

0.16

ClinPred

0.11

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.30

Mutation Taster

=2/98

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over