NM_000238.4:c.2405A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000238.4(KCNH2):​c.2405A>G​(p.Asn802Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 8.01
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 0 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000238.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
BS2
High AC in GnomAdExome4 at 18 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.2405A>G p.Asn802Ser missense_variant Exon 10 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.2405A>G p.Asn802Ser missense_variant Exon 10 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1
KCNH2ENST00000330883.9 linkc.1385A>G p.Asn462Ser missense_variant Exon 6 of 11 1 ENSP00000328531.4 Q12809-2
KCNH2ENST00000684241.1 linkn.3238A>G non_coding_transcript_exon_variant Exon 8 of 13

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461740
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 07, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 802 of the KCNH2 protein (p.Asn802Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT Syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 216326). 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. -

Cardiovascular phenotype Uncertain:1
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
Aug 18, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
1.9
.;L
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-4.1
D;D
REVEL
Pathogenic
0.86
Sift
Benign
0.047
D;D
Sift4G
Benign
0.10
T;D
Polyphen
0.76
P;D
Vest4
0.81
MutPred
0.67
.;Loss of catalytic residue at N802 (P = 0.1336);
MVP
0.89
MPC
2.0
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.45
gMVP
0.79

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

LitVar

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

Other links and lift over

dbSNP: rs863224632; hg19: chr7-150646131; API