Genetic Variant NM_001161352.2:c.92C>A (chr10-77637551-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001161352.2(KCNMA1):c.92C>A(p.Ala31Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,391,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.53

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4142114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.92C>A	p.Ala31Glu	missense_variant	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.92C>A	p.Ala31Glu	missense_variant	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000659

AC:

AN:

151682

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000116

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1391378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687312

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

36202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

35958

South Asian (SAS)

AF:

0.00

AC:

AN:

79578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1074468

Other (OTH)

AF:

0.00

AC:

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0054

.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Benign

0.026

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N;N;.;N;.;.;N;N;N;.;.;N;.;.

PhyloP100

3.5

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.26

.;.;.;.;.;N;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.31

.;.;.;.;.;T;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;T;.;.;.;.;D;D;D

Polyphen

0.069, 1.0, 0.11, 0.69, 0.25

.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;B;P;.;.;B;.;B;.;.;.;.;D;.;.

Vest4

0.55, 0.69, 0.62, 0.49, 0.73, 0.51, 0.72, 0.70, 0.75

MutPred

0.26

Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);

MVP

0.60

ClinPred

0.51

GERP RS

3.5

PromoterAI

-0.041

Neutral

(source)

Varity_R

0.23

gMVP

0.59

Mutation Taster

=76/24

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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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