rs1554425806

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000238.4(KCNH2):​c.1808G>A​(p.Gly603Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G603G) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Consequence

KCNH2
NM_000238.4 missense

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.681
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 4 ACMG points.

PM1
In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.1808G>A p.Gly603Asp missense_variant 7/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.1808G>A p.Gly603Asp missense_variant 7/151 NM_000238.4 ENSP00000262186 P1Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
34

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), LabcorpSep 06, 2023This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 603 of the KCNH2 protein (p.Gly603Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 26669661). ClinVar contains an entry for this variant (Variation ID: 456894). 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 disruptive. 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
0.26
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
.;D;D
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.37
N
LIST_S2
Uncertain
0.89
D;D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Benign
1.3
.;L;.
MutationTaster
Benign
0.78
D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.5
D;D;D
REVEL
Pathogenic
0.88
Sift
Benign
0.15
T;T;T
Sift4G
Uncertain
0.047
D;T;D
Polyphen
0.22
B;B;.
Vest4
0.59
MutPred
0.47
.;Gain of ubiquitination at K608 (P = 0.0605);.;
MVP
0.92
MPC
2.2
ClinPred
0.96
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.27
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs1554425806; hg19: chr7-150648673; API