Variant rs137853333 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3PP5_Moderate

The ENST00000286628.14(KCNMA1):c.1301A>G(p.Asp434Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 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 Pathogenic (★).

Frequency

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

Consequence

KCNMA1
ENST00000286628.14 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 8.02

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_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

PP5

Variant 10-77090433-T-C is Pathogenic according to our data. Variant chr10-77090433-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9427.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 linkuse as main transcript	c.1301A>G	p.Asp434Gly	missense_variant	10/28	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.1301A>G	p.Asp434Gly	missense_variant	10/28	1	NM_001161352.2	ENSP00000286628	A2	Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.000478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2005

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Benign

0.85

DEOGEN2

Benign

0.069

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

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.037

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;D

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.025

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.3

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

REVEL

Uncertain

0.63

Sift

Benign

0.58

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

Sift4G

Benign

0.40

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

Polyphen

0.0, 0.99, 0.0010, 0.019

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

Vest4

0.84, 0.93, 0.85, 0.84, 0.87, 0.85, 0.53, 0.76

MutPred

0.59

.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;.;.;.;.;.;Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;.;.;Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);.;.;Loss of stability (P = 0.0116);

MVP

0.98

MPC

2.6

ClinPred

0.81

GERP RS

5.7

Varity_R

0.86

gMVP

0.95

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