Genetic Variant KCNMA1:c.2710-19dupT (chr10-76944983-G-GA) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001161352.2(KCNMA1):c.2710-19dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00476 in 1,529,182 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 22 hom. )

Consequence

KCNMA1
NM_001161352.2 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.262

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 links:

KCNMA1-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

KCNMA1-AS1 links:

LOC124902466 (HGNC:):

LOC124902466 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 10-76944983-G-GA is Benign according to our data. Variant chr10-76944983-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445800.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 = 0.00993 (1479/148974) while in subpopulation AFR AF = 0.0333 (1350/40570). AF 95% confidence interval is 0.0318. There are 18 homozygotes in GnomAd4. There are 714 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.2710-19dupT		intron_variant	Intron 22 of 27	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.2710-19_2710-18insT		intron_variant	Intron 22 of 27	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.00994

AC:

1479

AN:

148864

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000406

Gnomad MID

AF:

0.00968

Gnomad NFE

AF:

0.000924

Gnomad OTH

AF:

0.00688

GnomAD2 exomes

AF:

0.00398

AC:

879

AN:

220710

AF XY:

0.00332

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.000219

Gnomad EAS exome

AF:

0.000499

Gnomad FIN exome

AF:

0.00173

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00190

GnomAD4 exome

AF:

0.00420

AC:

5796

AN:

1380208

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

2599

AN XY:

688020

show subpopulations

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

African (AFR)

AF:

0.0384

AC:

1204

AN:

31316

American (AMR)

AF:

0.00218

AC:

AN:

41776

Ashkenazi Jewish (ASJ)

AF:

0.00102

AC:

AN:

24530

East Asian (EAS)

AF:

0.000907

AC:

AN:

37492

South Asian (SAS)

AF:

0.00114

AC:

AN:

82600

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

50398

Middle Eastern (MID)

AF:

0.00385

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00377

AC:

3961

AN:

1050030

Other (OTH)

AF:

0.00512

AC:

290

AN:

56606

⚠️ 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: 0.337

Heterozygous variant carriers

553

1106

1660

2213

2766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00993

AC:

1479

AN:

148974

Hom.:

Cov.:

AF XY:

0.00984

AC XY:

714

AN XY:

72562

show subpopulations

African (AFR)

AF:

0.0333

AC:

1350

AN:

40570

American (AMR)

AF:

0.00300

AC:

AN:

14984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.000196

AC:

AN:

5090

South Asian (SAS)

AF:

0.00

AC:

AN:

4690

European-Finnish (FIN)

AF:

0.000406

AC:

AN:

9844

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000924

AC:

AN:

67100

Other (OTH)

AF:

0.00681

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00224

Hom.:

Bravo

AF:

0.0113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 07, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.26

Mutation Taster

=100/0

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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10-76944983-GA-GAA

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