Genetic Variant NM_001161352.2:c.541-66081G>A (chr10-77317337-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001161352.2(KCNMA1):c.541-66081G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,100 control chromosomes in the GnomAD database, including 3,466 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 0.21 ( 3466 hom., cov: 32)

Consequence

KCNMA1
NM_001161352.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0560

Publications

5 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Illumina, G2P
Liang-Wang syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
cerebellar atrophy, developmental delay, and seizures
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

KCNMA1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001161352.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.88).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
KCNMA1	NM_001161352.2	MANE Select	c.541-66081G>A	intron	N/A	NP_001154824.1	Q12791-1
KCNMA1	NM_001437422.1		c.673-66081G>A	intron	N/A	NP_001424351.1
KCNMA1	NM_001161353.2		c.541-66081G>A	intron	N/A	NP_001154825.1	Q12791-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.541-66081G>A	intron	N/A	ENSP00000286628.8	Q12791-1
KCNMA1	ENST00000626620.3	TSL:1	c.541-66081G>A	intron	N/A	ENSP00000485867.1	Q12791-2
KCNMA1	ENST00000639406.1	TSL:1	c.541-66081G>A	intron	N/A	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31208

AN:

151982

Hom.:

3460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.262

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.0152

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.222

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

GnomAD4 genome

AF:

0.205

AC:

31246

AN:

152100

Hom.:

3466

Cov.:

AF XY:

0.206

AC XY:

15334

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.175

AC:

7266

AN:

41486

American (AMR)

AF:

0.261

AC:

3995

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.148

AC:

511

AN:

3464

East Asian (EAS)

AF:

0.0152

AC:

AN:

5182

South Asian (SAS)

AF:

0.152

AC:

731

AN:

4822

European-Finnish (FIN)

AF:

0.262

AC:

2775

AN:

10576

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.220

AC:

14920

AN:

67970

Other (OTH)

AF:

0.225

AC:

475

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1275

2549

3824

5098

6373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.213

Hom.:

15069

Bravo

AF:

0.205

Asia WGS

AF:

0.0960

AC:

334

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.6

(source)

DANN

Benign

0.42

PhyloP100

0.056

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over