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rs199473008

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000238.4(KCNH2):c.2591A>G(p.Asp864Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D864D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense, splice_region

Scores

11
6
1
Splicing: ADA: 0.9997
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 7.99
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 2 ACMG points.

PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.2591A>G p.Asp864Gly missense_variant, splice_region_variant 10/15 ENST00000262186.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.2591A>G p.Asp864Gly missense_variant, splice_region_variant 10/151 NM_000238.4 P1Q12809-1
KCNH2ENST00000330883.9 linkuse as main transcriptc.1571A>G p.Asp524Gly missense_variant, splice_region_variant 6/111 Q12809-2
KCNH2ENST00000684241.1 linkuse as main transcriptn.3424A>G splice_region_variant, non_coding_transcript_exon_variant 8/13

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461826
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727212
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0

ClinVar

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

Submissions by phenotype

Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 02, 2023In 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 67417). This missense change has been observed in individual(s) with long QT syndrome (PMID: 20541041). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 864 of the KCNH2 protein (p.Asp864Gly). -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported as associated with Long QT syndrome in the following publications (PMID:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
Cadd
Pathogenic
36
Dann
Uncertain
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.7
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.97
D;D
Vest4
0.91
MutPred
0.42
.;Gain of methylation at R863 (P = 0.0642);
MVP
1.0
MPC
1.5
ClinPred
0.99
D
GERP RS
3.7
Varity_R
0.64
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: 1

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: rs199473008; hg19: chr7-150645945; API