rs41274568

Variant names:

• chr10-76949325-G-A
• rs41274568
• NM_001161352.2:c.2526C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001161352.2(KCNMA1):​c.2526C>T​(p.Val842Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,614,062 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (156 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.45
• Publications: 5 publications found

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]

KCNMA1-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

LOC124902466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.062).
• BP6: Variant 10-76949325-G-A is Benign according to our data. Variant chr10-76949325-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00902 (1373/152218) while in subpopulation NFE AF = 0.014 (953/68022). AF 95% confidence interval is 0.0133. There are 10 homozygotes in GnomAd4. There are 611 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.2526C>T	p.Val842Val	synonymous	Exon 22 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.2484C>T	p.Val828Val	synonymous	Exon 22 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2475C>T	p.Val825Val	synonymous	Exon 22 of 28	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.2526C>T	p.Val842Val	synonymous	Exon 22 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.2475C>T	p.Val825Val	synonymous	Exon 22 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.2361C>T	p.Val787Val	synonymous	Exon 22 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1373 AN: 152100 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00963 AC: 2416 AN: 250870 AF XY: 0.00972

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0120 AC: 17478 AN: 1461844 Hom.: 156 Cov.: 31 AF XY: 0.0118 AC XY: 8559 AN XY: 727220

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00577 AC: 258 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0440 AC: 1150 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00490 AC: 423 AN: 86256

European-Finnish (FIN) AF: 0.00268 AC: 143 AN: 53418

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14620 AN: 1111976

Other (OTH) AF: 0.0120 AC: 723 AN: 60394

GnomAD4 genome AF: 0.00902 AC: 1373 AN: 152218 Hom.: 10 Cov.: 32 AF XY: 0.00821 AC XY: 611 AN XY: 74412

African (AFR) AF: 0.00260 AC: 108 AN: 41526

American (AMR) AF: 0.00582 AC: 89 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 953 AN: 68022

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0124 Hom.: 40

Bravo AF: 0.00922

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0153

EpiControl AF: 0.0149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNMA1: BP4, BP7, BS1, BS2

Dec 27, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.28
DANN	Benign	0.82
PhyloP100		-1.4
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs41274568; hg19: chr10-78709083; COSMIC: COSV54271151;