10-77637591-CGCCGCCGCCGCCGCCGCTGCT-CGCCGCCGCCGCCGCCGCTGCTGCCGCCGCCGCCGCCGCTGCT

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.31_51dupAGCAGCGGCGGCGGCGGCGGC(p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000984 in 1,524,852 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G17G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Publications

1 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

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.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 28	NP_001154824.1
KCNMA1	NM_001437422.1		c.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	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.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 28	ENSP00000286628.8
KCNMA1	ENST00000626620.3	TSL:1	c.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 28	ENSP00000485867.1
KCNMA1	ENST00000639406.1	TSL:1	c.31_51dupAGCAGCGGCGGCGGCGGCGGC	p.Gly17_Gly18insSerSerGlyGlyGlyGlyGly	conservative_inframe_insertion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000102

AC:

AN:

1373212

Hom.:

Cov.:

AF XY:

0.00000886

AC XY:

AN XY:

677094

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30908

American (AMR)

AF:

0.00

AC:

AN:

34600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24516

East Asian (EAS)

AF:

0.00

AC:

AN:

35252

South Asian (SAS)

AF:

0.0000257

AC:

AN:

77862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.00000933

AC:

AN:

1072096

Other (OTH)

AF:

0.0000349

AC:

AN:

57274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000842214), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

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:

0.00000659

AC:

AN:

151640

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74036

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41296

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67830

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Sep 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1485982). This variant is not present in population databases (gnomAD no frequency). This variant, c.31_51dup, results in the insertion of 7 amino acid(s) of the KCNMA1 protein (p.Ser11_Gly17dup), but otherwise preserves the integrity of the reading frame.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

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

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