NM_000238.4:c.526C>T

Variant names:

Variant summary

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

The NM_000238.4(KCNH2):c.526C>T(p.Arg176Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,466,372 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:14B:5O:1

Conservation

PhyloP100: 1.14

Publications

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

KCNH2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000238.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 short QT syndrome type 1, long QT syndrome 2, short QT syndrome, Brugada syndrome, long QT syndrome.

PP3

REVEL computational evidence supports a deleterious effect, 0.718

BS2

High AC in GnomAd4 at 53 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	UniProt
KCNH2	NM_000238.4	MANE Select	c.526C>T	p.Arg176Trp	missense	Exon 4 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.238C>T	p.Arg80Trp	missense	Exon 2 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172056.3		c.526C>T	p.Arg176Trp	missense	Exon 4 of 9	NP_742053.1	Q12809-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.526C>T	p.Arg176Trp	missense	Exon 4 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000713710.1		c.526C>T	p.Arg176Trp	missense	Exon 4 of 15	ENSP00000519013.1	A0AAQ5BGR0
KCNH2	ENST00000713701.1		c.226C>T	p.Arg76Trp	missense	Exon 3 of 14	ENSP00000519004.1	A0AAQ5BGQ9

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000662

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000633

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000324

AC:

AN:

77224

AF XY:

0.000270

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:

0.00105

Gnomad NFE exome

AF:

0.000656

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000324

AC:

426

AN:

1314244

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

224

AN XY:

647814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26586

American (AMR)

AF:

0.00

AC:

AN:

25522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23038

East Asian (EAS)

AF:

0.00

AC:

AN:

28506

South Asian (SAS)

AF:

0.0000139

AC:

AN:

71696

European-Finnish (FIN)

AF:

0.000918

AC:

AN:

32688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4192

European-Non Finnish (NFE)

AF:

0.000367

AC:

384

AN:

1047616

Other (OTH)

AF:

0.000202

AC:

AN:

54400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000348

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41538

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000662

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000633

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000530

Hom.:

Bravo

AF:

0.000215

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Long QT syndrome 2 (5)

not specified (5)

Long QT syndrome (4)

not provided (3)

Cardiac arrhythmia (1)

Cardiovascular phenotype (1)

Prolonged QT interval (1)

Short QT syndrome type 1 (1)

Short QT syndrome type 1;C3150943:Long QT syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostArm

Benign

0.014

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.7

PhyloP100

1.1

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Varity_R

0.067

gMVP

0.54

Mutation Taster

=12/88

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over