10-77637505-AGAGGAGGAGGAG-AGAGGAGGAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS1

The NM_001161352.2(KCNMA1):c.135_137delCTC(p.Ser46del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,551,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.55

Publications

2 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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001161352.2

BP6

Variant 10-77637505-AGAG-A is Benign according to our data. Variant chr10-77637505-AGAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000475 (72/151532) while in subpopulation AFR AF = 0.0014 (58/41352). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.135_137delCTC	p.Ser46del	disruptive_inframe_deletion	Exon 1 of 28	ENST00000286628.14	NP_001154824.1	Q12791-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 link	c.135_137delCTC	p.Ser46del	disruptive_inframe_deletion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.000475

AC:

AN:

151420

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.000965

GnomAD2 exomes

AF:

0.00140

AC:

269

AN:

191788

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.000772

Gnomad ASJ exome

AF:

0.000228

Gnomad EAS exome

AF:

0.000781

Gnomad FIN exome

AF:

0.00409

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.000989

GnomAD4 exome

AF:

0.00201

AC:

2816

AN:

1399530

Hom.:

AF XY:

0.00193

AC XY:

1339

AN XY:

694840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00282

AC:

AN:

31948

American (AMR)

AF:

0.000366

AC:

AN:

40942

Ashkenazi Jewish (ASJ)

AF:

0.000557

AC:

AN:

25122

East Asian (EAS)

AF:

0.000562

AC:

AN:

37384

South Asian (SAS)

AF:

0.00105

AC:

AN:

81710

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

50256

Middle Eastern (MID)

AF:

0.000532

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00227

AC:

2422

AN:

1068652

Other (OTH)

AF:

0.00166

AC:

AN:

57872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

392

784

1177

1569

1961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

130

260

390

520

650

<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:

0.000475

AC:

AN:

151532

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

AN XY:

74054

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41352

American (AMR)

AF:

0.000197

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000197

AC:

AN:

5086

South Asian (SAS)

AF:

0.000417

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000885

AC:

AN:

67794

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00463

Hom.:

Bravo

AF:

0.000631

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 10, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 02, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=76/24

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over