rs41274568

chr10-76949325-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001161352.2(KCNMA1):c.2526C>T(p.Val842=) 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:6
• Conservation: PhyloP100: -1.45

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]

LOC124902466 (HGNC:):

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 10-76949325-G-A is Benign according to our data. Variant chr10-76949325-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-76949325-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.2526C>T	p.Val842=	synonymous_variant	22/28	ENST00000286628.14
LOC124902466	XR_007062207.1	n.740G>A		non_coding_transcript_exon_variant	3/3
KCNMA1-AS1	NR_120655.1	n.458-28285G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.2526C>T	p.Val842=	synonymous_variant	22/28	1	NM_001161352.2	A2
KCNMA1-AS1	ENST00000458661.6	n.426-28285G>A		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00963 AC: 2416 AN: 250870 Hom.: 23 AF XY: 0.00972 AC XY: 1318 AN XY: 135642

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 SAS exome AF: 0.00513

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

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.0440

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00490

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0120

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

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0136 Hom.: 10

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KCNMA1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.28
Dann	Benign	0.82

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