rs2116830

Positions:

• chr10-76886778-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001161352.2(KCNMA1):​c.*488C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,025,966 control chromosomes in the GnomAD database, including 18,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1789 hom., cov: 33)
  • Exomes 𝑓: 0.19 (16587 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.891

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-76886778-G-T is Benign according to our data. Variant chr10-76886778-G-T is described in ClinVar as [Benign]. Clinvar id is 300951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-76886778-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*488C>A		3_prime_UTR_variant	28/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.*488C>A		3_prime_UTR_variant	28/28	1	NM_001161352.2	ENSP00000286628	A2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20654 AN: 152050 Hom.: 1789 Cov.: 33

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.191 AC: 166525 AN: 873796 Hom.: 16587 Cov.: 32 AF XY: 0.190 AC XY: 77354 AN XY: 406118

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.000626

Gnomad4 SAS exome AF: 0.0425

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.136 AC: 20646 AN: 152170 Hom.: 1789 Cov.: 33 AF XY: 0.131 AC XY: 9742 AN XY: 74392

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.166

Alfa AF: 0.176 Hom.: 3454

Bravo AF: 0.134

Asia WGS AF: 0.0280 AC: 99 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.7
DANN	Benign	0.51

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: rs2116830; hg19: chr10-78646536;