rs1397556923
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001161352.2(KCNMA1):c.3416G>A(p.Arg1139Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
KCNMA1
NM_001161352.2 missense
NM_001161352.2 missense
Scores
15
1
3
Clinical Significance
Conservation
PhyloP100: 7.57
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNMA1. . Gene score misZ 5.0622 (greater than the threshold 3.09). Trascript score misZ 6.5162 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.893
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNMA1 | NM_001161352.2 | c.3416G>A | p.Arg1139Gln | missense_variant | 27/28 | ENST00000286628.14 | NP_001154824.1 | |
KCNMA1-AS1 | NR_120655.1 | n.238+1215C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNMA1 | ENST00000286628.14 | c.3416G>A | p.Arg1139Gln | missense_variant | 27/28 | 1 | NM_001161352.2 | ENSP00000286628 | A2 | |
KCNMA1-AS1 | ENST00000458661.6 | n.206+1215C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727216
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74268
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2017 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with KCNMA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 1081 of the KCNMA1 protein (p.Arg1081Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen
1.0
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;.;.;.;.;.;D;D;.;.;D;.;.;.
Vest4
0.97, 0.93, 0.95, 0.93, 0.84, 0.90
MutPred
0.74
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.0181);.;.;.;Loss of sheet (P = 0.0181);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
MPC
2.5
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at