Genetic Variant KCNMA1:p.Ser52del (chr10-77637487-GGAA-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001161352.2(KCNMA1):c.153_155delTTC(p.Ser52del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,600,558 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S51S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 5 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.05

Publications

3 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

generalized epilepsy-paroxysmal dyskinesia syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
Liang-Wang syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
cerebellar atrophy, developmental delay, and seizures
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

KCNMA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001161352.2

BP6

Variant 10-77637487-GGAA-G is Benign according to our data. Variant chr10-77637487-GGAA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193228.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00132 (201/152080) while in subpopulation EAS AF = 0.0172 (88/5126). AF 95% confidence interval is 0.0143. There are 3 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNMA1	NM_001161352.2	MANE Select	c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 28	NP_001154824.1
KCNMA1	NM_001437422.1		c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000286628.8
KCNMA1	ENST00000626620.3	TSL:1	c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000485867.1
KCNMA1	ENST00000639406.1	TSL:1	c.153_155delTTC	p.Ser52del	disruptive_inframe_deletion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

194

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00183

AC:

418

AN:

228072

AF XY:

0.00179

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.000214

Gnomad ASJ exome

AF:

0.000420

Gnomad EAS exome

AF:

0.0197

Gnomad FIN exome

AF:

0.000100

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.000702

GnomAD4 exome

AF:

0.000539

AC:

781

AN:

1448478

Hom.:

AF XY:

0.000539

AC XY:

388

AN XY:

719872

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

33210

American (AMR)

AF:

0.000229

AC:

AN:

43634

Ashkenazi Jewish (ASJ)

AF:

0.000309

AC:

AN:

25890

East Asian (EAS)

AF:

0.0119

AC:

469

AN:

39340

South Asian (SAS)

AF:

0.000354

AC:

AN:

84666

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52442

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000139

AC:

153

AN:

1103644

Other (OTH)

AF:

0.000818

AC:

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00132

AC:

201

AN:

152080

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41542

American (AMR)

AF:

0.000262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0172

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67956

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000563

Hom.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNMA1: BS1

Jan 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Aug 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNMA1-related disorder

Benign:1

Oct 07, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=66/34

polymorphism

(source)

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

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10-77637487-GGAAGAAGAA-GGAAGAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over