rs199472875

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000238.4(KCNH2):ā€‹c.769A>Cā€‹(p.Asn257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)

Consequence

KCNH2
NM_000238.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: -0.00800
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33192176).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.769A>C p.Asn257His missense_variant 4/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.769A>C p.Asn257His missense_variant 4/151 NM_000238.4 ENSP00000262186 P1Q12809-1
KCNH2ENST00000532957.5 linkuse as main transcriptn.992A>C non_coding_transcript_exon_variant 4/92
KCNH2ENST00000684241.1 linkuse as main transcriptn.1602A>C non_coding_transcript_exon_variant 2/13

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151772
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151772
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74152
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported in the following publications (PMID:14661677;PMID:19841300). -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 12, 2018This variant is associated with the following publications: (PMID: 19841300, 14661677) -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 27, 2022This variant is present in population databases (rs199472875, gnomAD 0.01%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67526). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 257 of the KCNH2 protein (p.Asn257His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.46
T;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.81
T;T
M_CAP
Pathogenic
0.92
D
MetaRNN
Benign
0.33
T;T
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
0.81
L;.
MutationTaster
Benign
0.88
N;N;N
PrimateAI
Pathogenic
0.94
D
PROVEAN
Benign
-0.66
N;.
REVEL
Uncertain
0.55
Sift
Benign
0.54
T;.
Sift4G
Benign
0.24
T;T
Polyphen
0.036
B;.
Vest4
0.20
MutPred
0.34
Loss of stability (P = 0.1355);.;
MVP
0.92
MPC
1.3
ClinPred
0.31
T
GERP RS
3.6
Varity_R
0.11
gMVP
0.53

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: rs199472875; hg19: chr7-150655294; API