10-76884892-C-CT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001161352.2(KCNMA1):c.*2373_*2374insA variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000964 in 1,381,982 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (176/150708) while in subpopulation EAS AF= 0.00857 (44/5136). AF 95% confidence interval is 0.00656. There are 2 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.*2373_*2374insA		3_prime_UTR_variant	28/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.*2373_*2374insA		3_prime_UTR_variant	28/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 176 AN: 150596 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00855

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.0000982

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.000962

GnomAD4 exome AF: 0.000939 AC: 1156 AN: 1231274 Hom.: 1 Cov.: 26 AF XY: 0.000949 AC XY: 572 AN XY: 602680

Gnomad4 AFR exome AF: 0.000473

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.000554

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.000376

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00117 AC: 176 AN: 150708 Hom.: 2 Cov.: 30 AF XY: 0.00124 AC XY: 91 AN XY: 73538

Gnomad4 AFR AF: 0.000462

Gnomad4 AMR AF: 0.00616

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00857

Gnomad4 SAS AF: 0.000212

Gnomad4 FIN AF: 0.0000982

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.000951

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs552322812; hg19: chr10-78644650;