rs914048941

Positions:

chr10-77637627-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_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 (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNMA1. . Gene score misZ 5.0622 (greater than the threshold 3.09). Trascript score misZ 6.5162 (greater than threshold 3.09). GenCC has associacion of gene with cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 linkuse as main transcript	c.16G>A	p.Gly6Ser	missense_variant	1/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 linkuse as main transcript	c.16G>A	p.Gly6Ser	missense_variant	1/28	1	NM_001161352.2	ENSP00000286628	A2	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

GnomAD3 exomes

AF:

0.0000326

AC:

AN:

122676

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

67130

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000968

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.000314

GnomAD4 genome

AF:

0.0000794

AC:

AN:

151228

Hom.:

Cov.:

AF XY:

0.0000948

AC XY:

AN XY:

73814

show subpopulations

Gnomad4 AFR

AF:

0.0000486

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2022

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. 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: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 532940). This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. 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 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). -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

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

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;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

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

Varity_R

0.13

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over