rs45586138

Positions:

• chr10-76891627-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.3240C>T​(p.Asn1080Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,054 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (32 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.269

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-76891627-G-A is Benign according to our data. Variant chr10-76891627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 284179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-76891627-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00362 (551/152308) while in subpopulation AMR AF= 0.00771 (118/15302). AF 95% confidence interval is 0.00658. There are 0 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.3240C>T	p.Asn1080Asn	synonymous_variant	26/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.3240C>T	p.Asn1080Asn	synonymous_variant	26/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00347 AC: 871 AN: 251002 Hom.: 4 AF XY: 0.00342 AC XY: 464 AN XY: 135682

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00447 AC: 6533 AN: 1461746 Hom.: 32 Cov.: 31 AF XY: 0.00441 AC XY: 3204 AN XY: 727184

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00606

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00352 AC XY: 262 AN XY: 74476

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00383 Hom.: 0

Bravo AF: 0.00431

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	KCNMA1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2015	- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:2

Likely 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 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.5
DANN	Benign	0.88

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: rs45586138; hg19: chr10-78651385;