rs914048941

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001161352.2(KCNMA1):c.16G>A(p.Gly6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,523,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G6G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5B:1

Conservation

PhyloP100: 0.939

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23657635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.16G>A	p.Gly6Ser	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.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.0000794

AC:

AN:

151228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000326

AC:

AN:

122676

AF XY:

0.0000298

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:

0.00

Gnomad NFE exome

AF:

0.0000869

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

185

AN:

1372060

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

676418

show subpopulations

African (AFR)

AF:

0.0000968

AC:

AN:

30984

American (AMR)

AF:

0.00

AC:

AN:

34642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24286

East Asian (EAS)

AF:

0.00

AC:

AN:

35368

South Asian (SAS)

AF:

0.00

AC:

AN:

77614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4816

European-Non Finnish (NFE)

AF:

0.000153

AC:

164

AN:

1072584

Other (OTH)

AF:

0.000314

AC:

AN:

57246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.0000794

AC:

AN:

151228

Hom.:

Cov.:

AF XY:

0.0000948

AC XY:

AN XY:

73814

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41140

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67706

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Aug 02, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Dec 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.16G>A (p.G6S) alteration is located in exon 1 (coding exon 1) of the KCNMA1 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 6 of the KCNMA1 protein (p.Gly6Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 532940). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0057

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

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.76

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;T;D

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.24

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

Benign

-0.80

MutationAssessor

Benign

0.0

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

PhyloP100

0.94

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.20

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

REVEL

Benign

0.27

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.71

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

Polyphen

0.021, 0.086, 0.036, 0.062, 0.97

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

Vest4

0.29, 0.30, 0.31, 0.27, 0.36, 0.34, 0.33, 0.37

MutPred

0.17

Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);Gain of glycosylation at G6 (P = 0.0016);

MVP

0.65

ClinPred

0.38

GERP RS

2.5

PromoterAI

-0.076

Neutral

(source)

Varity_R

0.13

gMVP

0.38

Mutation Taster

=86/14

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