rs199473669

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000238.4(KCNH2):​c.2707G>C​(p.Gly903Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

KCNH2
NM_000238.4 missense

Scores

6
6
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.2707G>C p.Gly903Arg missense_variant Exon 12 of 15 ENST00000262186.10 NP_000229.1 Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkc.2707G>C p.Gly903Arg missense_variant Exon 12 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1
KCNH2ENST00000330883.9 linkc.1687G>C p.Gly563Arg missense_variant Exon 8 of 11 1 ENSP00000328531.4 Q12809-2
KCNH2ENST00000684241.1 linkn.3540G>C non_coding_transcript_exon_variant Exon 10 of 13

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 22, 2024This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 903 of the KCNH2 protein (p.Gly903Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085, 27000522, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 960253). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 31557540, 34002542). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.43
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
.;T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Benign
1.7
.;L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.55
N;N
REVEL
Pathogenic
0.74
Sift
Benign
0.14
T;T
Sift4G
Benign
0.18
T;T
Polyphen
0.93
P;B
Vest4
0.57
MutPred
0.69
.;Gain of MoRF binding (P = 0.0295);
MVP
0.99
MPC
0.20
ClinPred
0.82
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.39
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199473669; hg19: chr7-150644952; API