Genetic Variant KCNMA1:c.379-21330A>G (chr10-77425353-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001161352.2(KCNMA1):c.379-21330A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 151,946 control chromosomes in the GnomAD database, including 19,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 19723 hom., cov: 32)

Consequence

KCNMA1
NM_001161352.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.91

Publications

6 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:

ENSG00000295562 (HGNC:):

ENSG00000295562 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.379-21330A>G		intron_variant	Intron 1 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.379-21330A>G		intron_variant	Intron 1 of 27	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74068

AN:

151826

Hom.:

19673

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.356

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.491

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.488

AC:

74173

AN:

151946

Hom.:

19723

Cov.:

AF XY:

0.484

AC XY:

35925

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.704

AC:

29152

AN:

41412

American (AMR)

AF:

0.495

AC:

7552

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1384

AN:

3472

East Asian (EAS)

AF:

0.261

AC:

1348

AN:

5166

South Asian (SAS)

AF:

0.528

AC:

2537

AN:

4806

European-Finnish (FIN)

AF:

0.360

AC:

3795

AN:

10556

Middle Eastern (MID)

AF:

0.473

AC:

138

AN:

292

European-Non Finnish (NFE)

AF:

0.396

AC:

26914

AN:

67958

Other (OTH)

AF:

0.487

AC:

1029

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1802

3604

5405

7207

9009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.362

Hom.:

1446

Bravo

AF:

0.509

Asia WGS

AF:

0.430

AC:

1492

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.044

(source)

DANN

Benign

0.41

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over