NM_001161352.2:c.48_56dupCGGCGGCGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001161352.2(KCNMA1):c.48_56dupCGGCGGCGG(p.Gly17_Gly19dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000374 in 1,524,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B: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 -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001161352.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.48_56dupCGGCGGCGG	p.Gly17_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.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.0000860

AC:

AN:

151112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000739

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000320

AC:

AN:

1373660

Hom.:

Cov.:

AF XY:

0.0000354

AC XY:

AN XY:

677468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30918

American (AMR)

AF:

0.00

AC:

AN:

34692

Ashkenazi Jewish (ASJ)

AF:

0.0000405

AC:

AN:

24708

East Asian (EAS)

AF:

0.00

AC:

AN:

35200

South Asian (SAS)

AF:

0.00

AC:

AN:

77968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5006

European-Non Finnish (NFE)

AF:

0.0000373

AC:

AN:

1071128

Other (OTH)

AF:

0.0000524

AC:

AN:

57282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000860

AC:

AN:

151216

Hom.:

Cov.:

AF XY:

0.0000947

AC XY:

AN XY:

73880

show subpopulations

African (AFR)

AF:

0.000170

AC:

AN:

41240

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.000198

AC:

AN:

5054

South Asian (SAS)

AF:

0.00

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0000739

AC:

AN:

67648

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:2

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.48_56dup, results in the insertion of 3 amino acid(s) of the KCNMA1 protein (p.Gly18_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: 841161). 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. -

Dec 06, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. -

not provided

Uncertain:1Benign:1

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In-frame insertion of 3 amino acids in a repetitive region with no known function -

not specified

Uncertain:1

Apr 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNMA1 c.48_56dupCGGCGGCGG (p.Gly18_Gly20dup) results in an in-frame duplication that is predicted to duplicate 3 amino acids into the encoded protein. The variant was absent in 114424 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.48_56dupCGGCGGCGG in individuals affected with Paroxysmal Nonkinesigenic Dyskinesia, 3, With Or Without Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 841161). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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