7-150947785-TC-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.2785delG(p.Glu929ArgfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 frameshift
NM_000238.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.34
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 7-150947785-TC-T is Pathogenic according to our data. Variant chr7-150947785-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 972416.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.2785delG | p.Glu929ArgfsTer45 | frameshift | Exon 12 of 15 | NP_000229.1 | A0A090N8Q0 | ||
| KCNH2 | c.2497delG | p.Glu833ArgfsTer45 | frameshift | Exon 10 of 13 | NP_001393682.1 | Q12809-7 | |||
| KCNH2 | c.1765delG | p.Glu589ArgfsTer45 | frameshift | Exon 8 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.2785delG | p.Glu929ArgfsTer45 | frameshift | Exon 12 of 15 | ENSP00000262186.5 | Q12809-1 | ||
| KCNH2 | TSL:1 | c.1765delG | p.Glu589ArgfsTer45 | frameshift | Exon 8 of 11 | ENSP00000328531.4 | Q12809-2 | ||
| KCNH2 | c.2719delG | p.Glu907ArgfsTer45 | frameshift | Exon 12 of 15 | ENSP00000519013.1 | A0AAQ5BGR0 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.23e-7 AC: 1AN: 1382686Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 681838 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:
1382686
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
681838
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:
31428
American (AMR)
AF:
AC:
0
AN:
35538
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25064
East Asian (EAS)
AF:
AC:
0
AN:
35626
South Asian (SAS)
AF:
AC:
0
AN:
78984
European-Finnish (FIN)
AF:
AC:
1
AN:
37390
Middle Eastern (MID)
AF:
AC:
0
AN:
4192
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1076874
Other (OTH)
AF:
AC:
0
AN:
57590
⚠️ 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: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Long QT syndrome (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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