rs146284716

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The ENST00000262186.10(KCNH2):​c.431A>T​(p.Asp144Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,988 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D144D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

KCNH2
ENST00000262186.10 missense

Scores

2
5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.753
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1
In a domain PAC (size 52) in uniprot entity KCNH2_HUMAN there are 24 pathogenic changes around while only 5 benign (83%) in ENST00000262186.10
BP4
Computational evidence support a benign effect (MetaRNN=0.20533708).
BP6
Variant 7-150959613-T-A is Benign according to our data. Variant chr7-150959613-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 16 AD,Digenic gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.431A>T p.Asp144Val missense_variant 3/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.431A>T p.Asp144Val missense_variant 3/151 NM_000238.4 ENSP00000262186 P1Q12809-1
KCNH2ENST00000532957.5 linkuse as main transcriptn.654A>T non_coding_transcript_exon_variant 3/92
KCNH2ENST00000684241.1 linkuse as main transcriptn.1264A>T non_coding_transcript_exon_variant 1/13

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152130
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000478
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
251152
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461858
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152130
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.000338
Gnomad4 AMR
AF:
0.0000654
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:
0.000478
Bravo
AF:
0.000128
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 144 of the KCNH2 protein (p.Asp144Val). This variant is present in population databases (rs146284716, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 526910). 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. 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. -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 13, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 01, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
KCNH2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 23, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiac arrhythmia Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 06, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.39
T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.77
T
M_CAP
Pathogenic
0.59
D
MetaRNN
Benign
0.21
T
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.46
Sift
Benign
0.17
T
Sift4G
Benign
0.23
T
Polyphen
0.94
P
Vest4
0.36
MVP
0.81
MPC
1.4
ClinPred
0.060
T
GERP RS
4.7
Varity_R
0.19
gMVP
0.63

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: rs146284716; hg19: chr7-150656701; API