NM_001161352.2:c.54_56dupCGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS1

The NM_001161352.2(KCNMA1):c.54_56dupCGG(p.Gly19dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000563 in 1,524,852 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 5.59

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001161352.2

BP6

Variant 10-77637586-T-TCCG is Benign according to our data. Variant chr10-77637586-T-TCCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193225.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000873 (132/151214) while in subpopulation AMR AF = 0.00203 (31/15238). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAd4. There are 51 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.54_56dupCGG	p.Gly19dup	disruptive_inframe_insertion	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.54_56dupCGG	p.Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

131

AN:

151110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000948

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00327

Gnomad NFE

AF:

0.000724

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000655

AC:

AN:

114424

AF XY:

0.000604

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00167

Gnomad EAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000479

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.000529

AC:

726

AN:

1373638

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

346

AN XY:

677458

show subpopulations

African (AFR)

AF:

0.00100

AC:

AN:

30918

American (AMR)

AF:

0.000980

AC:

AN:

34686

Ashkenazi Jewish (ASJ)

AF:

0.00198

AC:

AN:

24704

East Asian (EAS)

AF:

0.000710

AC:

AN:

35200

South Asian (SAS)

AF:

0.000410

AC:

AN:

77966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36758

Middle Eastern (MID)

AF:

0.000200

AC:

AN:

5006

European-Non Finnish (NFE)

AF:

0.000467

AC:

500

AN:

1071120

Other (OTH)

AF:

0.000943

AC:

AN:

57280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000873

AC:

132

AN:

151214

Hom.:

Cov.:

AF XY:

0.000690

AC XY:

AN XY:

73878

show subpopulations

African (AFR)

AF:

0.000946

AC:

AN:

41238

American (AMR)

AF:

0.00203

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

3454

East Asian (EAS)

AF:

0.000198

AC:

AN:

5054

South Asian (SAS)

AF:

0.000210

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00352

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000724

AC:

AN:

67648

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000364

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Apr 28, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Jul 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame duplication of 1 amino acid in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNMA1: BP3, BS2 -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.54_56dup, results in the insertion of 1 amino acid(s) of the KCNMA1 protein (p.Gly20dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 193225). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Mar 31, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNMA1-related disorder

Benign:1

Sep 08, 2022

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). -

Infantile epileptic dyskinetic encephalopathy;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.6

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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