rs1385959174
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.2677_2680dupAGGC(p.Arg894GlnfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000087 in 1,149,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R894R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 8.7e-7 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 frameshift
NM_000238.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.05
Publications
2 publications found
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 syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- long QT syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- short QT syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- short QT syndrome type 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- Brugada syndromeInheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-150948455-C-CGCCT is Pathogenic according to our data. Variant chr7-150948455-C-CGCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 519280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KCNH2 | MANE Select | c.2677_2680dupAGGC | p.Arg894GlnfsTer27 | frameshift | Exon 11 of 15 | NP_000229.1 | A0A090N8Q0 | ||
| KCNH2 | c.2389_2392dupAGGC | p.Arg798GlnfsTer27 | frameshift | Exon 9 of 13 | NP_001393682.1 | Q12809-7 | |||
| KCNH2 | c.1657_1660dupAGGC | p.Arg554GlnfsTer27 | frameshift | Exon 7 of 11 | NP_742054.1 | Q12809-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KCNH2 | TSL:1 MANE Select | c.2677_2680dupAGGC | p.Arg894GlnfsTer27 | frameshift | Exon 11 of 15 | ENSP00000262186.5 | Q12809-1 | ||
| KCNH2 | TSL:1 | c.1657_1660dupAGGC | p.Arg554GlnfsTer27 | frameshift | Exon 7 of 11 | ENSP00000328531.4 | Q12809-2 | ||
| KCNH2 | c.2611_2614dupAGGC | p.Arg872GlnfsTer27 | frameshift | Exon 11 of 15 | ENSP00000519013.1 | A0AAQ5BGR0 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 8.70e-7 AC: 1AN: 1149748Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 576204 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1149748
Hom.:
Cov.:
37
AF XY:
AC XY:
0
AN XY:
576204
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
25164
American (AMR)
AF:
AC:
0
AN:
38902
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
18300
East Asian (EAS)
AF:
AC:
0
AN:
20214
South Asian (SAS)
AF:
AC:
0
AN:
82196
European-Finnish (FIN)
AF:
AC:
0
AN:
29552
Middle Eastern (MID)
AF:
AC:
0
AN:
4554
European-Non Finnish (NFE)
AF:
AC:
1
AN:
887130
Other (OTH)
AF:
AC:
0
AN:
43736
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Cardiovascular phenotype (1)
1
-
-
Long QT syndrome (1)
1
-
-
Long QT syndrome 2 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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