Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1
The NM_001161352.2(KCNMA1):c.2484+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
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]
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
Variant 10-76953794-C-T is Benign according to our data. Variant chr10-76953794-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 532948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00163 (249/152300) while in subpopulation AFR AF= 0.00585 (243/41558). AF 95% confidence interval is 0.00524. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Cerebellar atrophy, developmental delay, and seizures;C5231421:Epilepsy, idiopathic generalized, susceptibility to, 16;C5231479:Liang-Wang syndrome;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
May 26, 2022
This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.5% (243/41436) (https://gnomad.broadinstitute.org/variant/10-76953794-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Benign (Variation ID:532948). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools suggest that this variant may not affect splicing. Further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
KCNMA1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Oct 25, 2022
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -