Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1
The NM_001161352.2(KCNMA1):c.2965C>T(p.Arg989Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,613,638 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R989H) has been classified as Uncertain significance.
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]
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
Missense variant where missense usually causes diseases, KCNMA1
BP4
Computational evidence support a benign effect (MetaRNN=0.07854259).
BP6
Variant 10-76914987-G-A is Benign according to our data. Variant chr10-76914987-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499429.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000414 (63/152262) while in subpopulation AFR AF= 0.00147 (61/41558). AF 95% confidence interval is 0.00117. There are 1 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.