10-77637505-AGAGGAG-AGAGGAGGAG

Position:

• chr10-77637505-AGAGGAG-AGAGGAGGAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):​c.135_137dupCTC​(p.Ser46dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,572,876 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (19 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.55

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 -16 ACMG points.

• BP6: Variant 10-77637505-A-AGAG is Benign according to our data. Variant chr10-77637505-A-AGAG is described in ClinVar as [Likely_benign]. Clinvar id is 167204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00458 (694/151554) while in subpopulation EAS AF= 0.0313 (159/5086). AF 95% confidence interval is 0.0273. There are 4 homozygotes in gnomad4. There are 353 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.135_137dupCTC	p.Ser46dup	disruptive_inframe_insertion	1/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.135_137dupCTC	p.Ser46dup	disruptive_inframe_insertion	1/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 696 AN: 151440 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00296

Gnomad ASJ AF: 0.00953

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00590

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00724

GnomAD3 exomes AF: 0.00518 AC: 993 AN: 191788 Hom.: 4 AF XY: 0.00495 AC XY: 512 AN XY: 103404

Gnomad AFR exome AF: 0.000351

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00934

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00611

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00692

GnomAD4 exome AF: 0.00365 AC: 5185 AN: 1421322 Hom.: 19 Cov.: 27 AF XY: 0.00372 AC XY: 2627 AN XY: 705752

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00911

Gnomad4 EAS exome AF: 0.0359

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00458 AC: 694 AN: 151554 Hom.: 4 Cov.: 33 AF XY: 0.00477 AC XY: 353 AN XY: 74072

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00953

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00590

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.00716

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KCNMA1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2019	This variant is associated with the following publications: (PMID: 26603346) -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

KCNMA1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs572827902; hg19: chr10-79397263;