10-77012032-TA-TAA
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001161352.2(KCNMA1):c.2026dupT(p.Tyr676LeufsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,592 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: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KCNMA1
NM_001161352.2 frameshift
NM_001161352.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
Publications
5 publications found
Genes affected
KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]
KCNMA1 Gene-Disease associations (from GenCC):
- generalized epilepsy-paroxysmal dyskinesia syndromeInheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
- Liang-Wang syndromeInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- cerebellar atrophy, developmental delay, and seizuresInheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 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 10-77012032-T-TA is Pathogenic according to our data. Variant chr10-77012032-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 437872.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001161352.2. 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 |
|---|---|---|---|---|---|---|---|---|---|
| KCNMA1 | MANE Select | c.2026dupT | p.Tyr676LeufsTer7 | frameshift | Exon 18 of 28 | NP_001154824.1 | Q12791-1 | ||
| KCNMA1 | c.2158dupT | p.Tyr720LeufsTer7 | frameshift | Exon 19 of 28 | NP_001424351.1 | ||||
| KCNMA1 | c.2026dupT | p.Tyr676LeufsTer7 | frameshift | Exon 18 of 28 | NP_001154825.1 | Q12791-2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KCNMA1 | TSL:1 MANE Select | c.2026dupT | p.Tyr676LeufsTer7 | frameshift | Exon 18 of 28 | ENSP00000286628.8 | Q12791-1 | ||
| KCNMA1 | TSL:1 | c.2026dupT | p.Tyr676LeufsTer7 | frameshift | Exon 18 of 28 | ENSP00000485867.1 | Q12791-2 | ||
| KCNMA1 | TSL:1 | c.2026dupT | p.Tyr676LeufsTer7 | frameshift | Exon 18 of 29 | ENSP00000491732.1 | B7ZMF5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250760 AF XY: 0.00000738 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
250760
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461592Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727114 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1461592
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
727114
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:
33474
American (AMR)
AF:
AC:
1
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26124
East Asian (EAS)
AF:
AC:
0
AN:
39660
South Asian (SAS)
AF:
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
AC:
0
AN:
53382
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111836
Other (OTH)
AF:
AC:
0
AN:
60380
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
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
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Cerebellar atrophy, developmental delay, and seizures (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
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.