7-150947385-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000238.4(KCNH2):​c.3095G>T​(p.Arg1032Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1032W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNH2
NM_000238.4 missense

Scores

5
7
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.605

Publications

2 publications found
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]
KCNH2 Gene-Disease associations (from GenCC):
  • long QT syndrome
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • long QT syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • short QT syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
  • short QT syndrome type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • Brugada syndrome
    Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 29 uncertain in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.3095G>T p.Arg1032Leu missense_variant Exon 13 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.3095G>T p.Arg1032Leu missense_variant Exon 13 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
146460
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1397074
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
689092
African (AFR)
AF:
0.00
AC:
0
AN:
31744
American (AMR)
AF:
0.00
AC:
0
AN:
35692
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25112
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36004
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46978
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5256
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1079130
Other (OTH)
AF:
0.00
AC:
0
AN:
57914
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000202
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
CardioboostArm
Benign
0.000061
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
.;D
Eigen
Uncertain
0.20
Eigen_PC
Benign
0.12
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.8
.;L
PhyloP100
0.60
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.4
N;D
REVEL
Uncertain
0.64
Sift
Benign
0.72
T;T
Sift4G
Benign
0.38
T;T
Polyphen
1.0
D;D
Vest4
0.56
MutPred
0.37
.;Loss of solvent accessibility (P = 0.001);
MVP
0.86
MPC
0.73
ClinPred
0.91
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.39
gMVP
0.59
Mutation Taster
=25/75
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs199473020; hg19: chr7-150644473; API