Genetic Variant KCNH2:p.Arg887Ser (chr7-150948477-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM5PP2PP3BS2

The NM_000238.4(KCNH2):c.2659C>A(p.Arg887Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000891 in 1,459,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R887H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

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: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150948476-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67423.

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, 0.768

BS2

High AC in GnomAdExome4 at 13 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.2659C>A	p.Arg887Ser	missense	Exon 11 of 15	NP_000229.1	A0A090N8Q0
KCNH2	NM_001406753.1		c.2371C>A	p.Arg791Ser	missense	Exon 9 of 13	NP_001393682.1	Q12809-7
KCNH2	NM_172057.3		c.1639C>A	p.Arg547Ser	missense	Exon 7 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.2659C>A	p.Arg887Ser	missense	Exon 11 of 15	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9	TSL:1	c.1639C>A	p.Arg547Ser	missense	Exon 7 of 11	ENSP00000328531.4	Q12809-2
KCNH2	ENST00000713710.1		c.2593C>A	p.Arg865Ser	missense	Exon 11 of 15	ENSP00000519013.1	A0AAQ5BGR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

249022

AF XY:

0.00

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1459630

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111622

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

CardioboostArm

Benign

0.0088

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.77

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

PhyloP100

4.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.81

Sift

Benign

0.045

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.53

MutPred

0.41

Gain of phosphorylation at R887 (P = 0.0085)

MVP

0.97

MPC

0.64

ClinPred

0.82

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.88

Mutation Taster

=25/75

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

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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