rs45527834

Positions:

• chr10-76891672-G-A
• chr10-76891672-G-C

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.3195C>T​(p.Thr1065Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00787 in 1,614,022 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (67 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.12

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=-0.68).
• BP6: Variant 10-76891672-G-A is Benign according to our data. Variant chr10-76891672-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-76891672-G-A is described in Lovd as [Benign]. Variant chr10-76891672-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00573 (872/152270) while in subpopulation NFE AF= 0.00948 (645/68004). AF 95% confidence interval is 0.00888. There are 5 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.3195C>T	p.Thr1065Thr	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.3195C>T	p.Thr1065Thr	synonymous_variant	26/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00948

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00570 AC: 1431 AN: 250884 Hom.: 7 AF XY: 0.00585 AC XY: 793 AN XY: 135630

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00283

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00809 AC: 11823 AN: 1461752 Hom.: 67 Cov.: 31 AF XY: 0.00789 AC XY: 5734 AN XY: 727190

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.00308

Gnomad4 NFE exome AF: 0.00925

Gnomad4 OTH exome AF: 0.00669

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74446

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00948

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00643 Hom.: 1

Bravo AF: 0.00529

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KCNMA1: BP4, BP7, BS2; KCNMA1-AS1: BS2 -
Likely 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	0.43
DANN	Benign	0.86

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: rs45527834; hg19: chr10-78651430;