10-77184852-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001161352.2(KCNMA1):c.667G>A(p.Val223Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,611,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.05

Publications

2 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.667G>A	p.Val223Met	missense_variant	Exon 4 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 link	c.667G>A	p.Val223Met	missense_variant	Exon 4 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

251010

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459852

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1110282

Other (OTH)

AF:

0.0000166

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

ExAC

AF:

0.00000824

AC:

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

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 223 of the KCNMA1 protein (p.Val223Met). This variant is present in population databases (rs779829350, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464303). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

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;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.81

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;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.1

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L;L;.;.;.;.;.;L;.;.;.;L;L;L;.;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.4

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

REVEL

Uncertain

0.62

Sift

Benign

0.15

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

Sift4G

Benign

0.17

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

Polyphen

0.051, 0.41, 0.082, 0.49, 0.041

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

Vest4

0.60, 0.67, 0.61, 0.61, 0.65, 0.58, 0.51, 0.51

MutPred

0.74

.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;.;.;.;.;.;Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;.;.;Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);Loss of catalytic residue at V223 (P = 0.2151);.;Loss of catalytic residue at V223 (P = 0.2151);

MVP

1.0

MPC

2.1

ClinPred

0.78

GERP RS

5.3

PromoterAI

0.045

Neutral

(source)

Varity_R

0.12

gMVP

0.87

Mutation Taster

=53/47

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over