rs45617636

chr10-77090414-G-Achr10-77090414-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001161352.2(KCNMA1):c.1320C>T(p.Ile440=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,610,452 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.132

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-77090414-G-A is Benign according to our data. Variant chr10-77090414-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 289603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-77090414-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00146 (222/152236) while in subpopulation NFE AF= 0.00241 (164/68020). AF 95% confidence interval is 0.00211. There are 1 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.1320C>T	p.Ile440=	synonymous_variant	10/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1320C>T	p.Ile440=	synonymous_variant	10/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00198 AC: 497 AN: 251288 Hom.: 1 AF XY: 0.00210 AC XY: 285 AN XY: 135812

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00332

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00203 AC: 2966 AN: 1458216 Hom.: 3 Cov.: 30 AF XY: 0.00202 AC XY: 1466 AN XY: 725718

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00230

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152236 Hom.: 1 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74430

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 05, 2016	- -
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	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 02, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 19, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KCNMA1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.8
Dann	Benign	0.76

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: rs45617636; hg19: chr10-78850172; COSMIC: COSV54238071;