10-76885309-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001161352.2(KCNMA1):c.*1957C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 865,032 control chromosomes in the GnomAD database, including 268,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.80 (48763 hom., cov: 28)
  • Exomes 𝑓: 0.78 (220093 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.449

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-76885309-G-A is Benign according to our data. Variant chr10-76885309-G-A is described in ClinVar as [Benign]. Clinvar id is 300927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.*1957C>T		3_prime_UTR_variant	28/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.*1957C>T		3_prime_UTR_variant	28/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.804 AC: 119662 AN: 148894 Hom.: 48735 Cov.: 28

Gnomad AFR AF: 0.905

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.732

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.782 AC: 560354 AN: 716114 Hom.: 220093 Cov.: 9 AF XY: 0.783 AC XY: 261077 AN XY: 333562

Gnomad4 AFR exome AF: 0.914

Gnomad4 AMR exome AF: 0.651

Gnomad4 ASJ exome AF: 0.758

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.891

Gnomad4 NFE exome AF: 0.787

Gnomad4 OTH exome AF: 0.757

GnomAD4 genome AF: 0.804 AC: 119707 AN: 148918 Hom.: 48763 Cov.: 28 AF XY: 0.800 AC XY: 58051 AN XY: 72598

Gnomad4 AFR AF: 0.905

Gnomad4 AMR AF: 0.706

Gnomad4 ASJ AF: 0.761

Gnomad4 EAS AF: 0.499

Gnomad4 SAS AF: 0.613

Gnomad4 FIN AF: 0.867

Gnomad4 NFE AF: 0.795

Gnomad4 OTH AF: 0.767

Alfa AF: 0.788 Hom.: 24662

Bravo AF: 0.795

Asia WGS AF: 0.618 AC: 2142 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.4
Dann	Benign	0.36

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: rs7073015; hg19: chr10-78645067; COSMIC: COSV54292767; COSMIC: COSV54292767;