rs1131824

chr10-77184832-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001161352.2(KCNMA1):c.687C>T(p.Phe229=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,600,698 control chromosomes in the GnomAD database, including 108,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15184 hom., cov: 32)
  • Exomes 𝑓: 0.35 (93170 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.40

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-77184832-G-A is Benign according to our data. Variant chr10-77184832-G-A is described in ClinVar as [Benign]. Clinvar id is 129328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-77184832-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.687C>T	p.Phe229=	synonymous_variant	4/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.687C>T	p.Phe229=	synonymous_variant	4/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64599 AN: 151846 Hom.: 15161 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.383

GnomAD3 exomes AF: 0.348 AC: 87164 AN: 250790 Hom.: 16512 AF XY: 0.346 AC XY: 46955 AN XY: 135522

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.267

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.352 AC: 510383 AN: 1448734 Hom.: 93170 Cov.: 30 AF XY: 0.351 AC XY: 253401 AN XY: 721448

Gnomad4 AFR exome AF: 0.636

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.425 AC: 64660 AN: 151964 Hom.: 15184 Cov.: 32 AF XY: 0.423 AC XY: 31414 AN XY: 74268

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.379

Alfa AF: 0.369 Hom.: 19140

Bravo AF: 0.428

Asia WGS AF: 0.313 AC: 1086 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.359

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:3

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2014	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

Cerebellar atrophy, developmental delay, and seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Liang-Wang syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	10
Dann	Benign	0.77

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: rs1131824; hg19: chr10-78944590; COSMIC: COSV54248693; COSMIC: COSV54248693;