GeneBe

rs199472855

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong

The NM_000238.4(KCNH2):​c.299G>T​(p.Arg100Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R100Q) has been classified as Likely pathogenic.

Frequency

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

Consequence

KCNH2
NM_000238.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Publications

5 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), G2P, Ambry Genetics
  • short QT syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • 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: Pathogenic. The variant received 11 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 27 uncertain in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-150974719-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67460.
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, 0.976

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
KCNH2
NM_000238.4
MANE Select
c.299G>Tp.Arg100Leu
missense
Exon 2 of 15NP_000229.1A0A090N8Q0
KCNH2
NM_172056.3
c.299G>Tp.Arg100Leu
missense
Exon 2 of 9NP_742053.1Q12809-5
KCNH2
NM_001406755.1
c.122G>Tp.Arg41Leu
missense
Exon 2 of 9NP_001393684.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
KCNH2
ENST00000262186.10
TSL:1 MANE Select
c.299G>Tp.Arg100Leu
missense
Exon 2 of 15ENSP00000262186.5Q12809-1
KCNH2
ENST00000713710.1
c.299G>Tp.Arg100Leu
missense
Exon 2 of 15ENSP00000519013.1A0AAQ5BGR0
KCNH2
ENST00000945647.1
c.299G>Tp.Arg100Leu
missense
Exon 2 of 14ENSP00000615706.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1445036
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
717998
African (AFR)
AF:
0.00
AC:
0
AN:
33084
American (AMR)
AF:
0.00
AC:
0
AN:
43486
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25830
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38958
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84698
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50648
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4332
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1104574
Other (OTH)
AF:
0.00
AC:
0
AN:
59426
GnomAD4 genome
Cov.:
33

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H
PhyloP100
1.6
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.012
D
Sift4G
Uncertain
0.022
D
Polyphen
0.58
P
Vest4
0.72
MutPred
0.83
Loss of methylation at K101 (P = 0.1458)
MVP
0.98
MPC
2.2
ClinPred
0.98
D
GERP RS
4.4
Varity_R
0.87
gMVP
0.95
Mutation Taster
=43/57
disease causing

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

Other links and lift over

dbSNP: rs199472855; hg19: chr7-150671807; API