rs77602559

chr10-77637609-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):c.34A>G(p.Ser12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,520,716 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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: 0.0018 (4 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 0.101

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KCNMA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0055193007).
• BP6: Variant 10-77637609-T-C is Benign according to our data. Variant chr10-77637609-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 193223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-77637609-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0057 (851/149174) while in subpopulation AFR AF= 0.0147 (597/40538). AF 95% confidence interval is 0.0137. There are 5 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.34A>G	p.Ser12Gly	missense_variant	1/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.34A>G	p.Ser12Gly	missense_variant	1/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 850 AN: 149072 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00242

Gnomad SAS AF: 0.000866

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00671

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00491

GnomAD3 exomes AF: 0.00204 AC: 255 AN: 125036 Hom.: 1 AF XY: 0.00200 AC XY: 137 AN XY: 68450

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00140

Gnomad SAS exome AF: 0.000803

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00182 AC: 2496 AN: 1371542 Hom.: 4 Cov.: 33 AF XY: 0.00178 AC XY: 1201 AN XY: 676296

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.00379

Gnomad4 ASJ exome AF: 0.00163

Gnomad4 EAS exome AF: 0.00187

Gnomad4 SAS exome AF: 0.000860

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00570 AC: 851 AN: 149174 Hom.: 5 Cov.: 32 AF XY: 0.00539 AC XY: 393 AN XY: 72928

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00531

Gnomad4 ASJ AF: 0.00146

Gnomad4 EAS AF: 0.00243

Gnomad4 SAS AF: 0.000867

Gnomad4 FIN AF: 0.00116

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00485

Alfa AF: 0.00589 Hom.: 0

Bravo AF: 0.00637

ExAC AF: 0.000243 AC: 12

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2020	- -

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KCNMA1: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	This variant is associated with the following publications: (PMID: 19266219) -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

KCNMA1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	15
Dann	Benign	0.76
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0055	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.87	D
Polyphen		0.0	.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;B;B;.;.;B;.;B;.;.;.;.;B;.;.
Vest4		0.21, 0.23, 0.20, 0.17, 0.22, 0.21, 0.28, 0.20, 0.23
MVP		0.65
ClinPred		0.079	T
GERP RS		-1.6
Varity_R		0.066
gMVP		0.32

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: rs77602559; hg19: chr10-79397367;