rs200474297

Positions:

chr10-77637554-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_001161352.2(KCNMA1):c.89A>G(p.His30Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000682 in 1,543,398 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H30H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 0 hom. )

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.88

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:

KCNMA1 (HGNC:):

KCNMA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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=0.03433919).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000395 (60/151816) while in subpopulation NFE AF= 0.000648 (44/67922). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 linkuse as main transcript	c.89A>G	p.His30Arg	missense_variant	1/28	ENST00000286628.14	NP_001154824.1	Q12791-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 linkuse as main transcript	c.89A>G	p.His30Arg	missense_variant	1/28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000648

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000241

AC:

AN:

149244

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

79802

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:

0.00105

Gnomad NFE exome

AF:

0.000416

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000714

AC:

993

AN:

1391582

Hom.:

Cov.:

AF XY:

0.000710

AC XY:

488

AN XY:

687174

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000794

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000952

Gnomad4 NFE exome

AF:

0.000863

Gnomad4 OTH exome

AF:

0.000293

GnomAD4 genome

AF:

0.000395

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.000418

AC XY:

AN XY:

74144

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000850

Gnomad4 NFE

AF:

0.000648

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000283

ExAC

AF:

0.000114

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	In silico analysis supports 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	Revvity Omics, Revvity	May 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.0074

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

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.055

FATHMM_MKL

Uncertain

0.77

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

0.83

MetaRNN

Benign

0.034

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

-0.71

MutationAssessor

Benign

0.0

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

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.37

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

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

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

Sift4G

Benign

0.092

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

Polyphen

0.0010, 0.24, 0.0020, 0.85, 0.0080, 0.61

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

Vest4

0.21, 0.34, 0.31, 0.20, 0.35, 0.20, 0.38, 0.35, 0.36

MutPred

0.28

Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);Gain of MoRF binding (P = 0.0122);

MVP

0.60

ClinPred

0.23

GERP RS

3.5

Varity_R

0.13

gMVP

0.41

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