dbSNP rs199472866: KCNH2:p.Arg164Pro (chr7-150958484-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000238.4(KCNH2):c.491G>C(p.Arg164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,320,276 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R164H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.99

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.491G>C	p.Arg164Pro	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.491G>C	p.Arg164Pro	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.57e-7

AC:

AN:

1320276

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

650884

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26894

American (AMR)

AF:

0.00

AC:

AN:

26672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23316

East Asian (EAS)

AF:

0.00

AC:

AN:

28588

South Asian (SAS)

AF:

0.00

AC:

AN:

72512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4328

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050428

Other (OTH)

AF:

0.0000183

AC:

AN:

54716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.2

PhyloP100

3.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.80

Sift

Benign

0.22

Sift4G

Benign

0.20

Polyphen

1.0

Vest4

0.88

MutPred

0.66

Loss of MoRF binding (P = 9e-04);

MVP

0.91

MPC

2.5

ClinPred

0.96

GERP RS

3.9

Varity_R

0.48

gMVP

0.77

Mutation Taster

=8/92

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over