dbSNP rs1554829003: KCNMA1:p.Gly375Arg (chr10-77110181-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001161352.2(KCNMA1):c.1123G>A(p.Gly375Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G375W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.90

Publications

1 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 10-77110181-C-T is Pathogenic according to our data. Variant chr10-77110181-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNMA1	NM_001161352.2	MANE Select	c.1123G>A	p.Gly375Arg	missense	Exon 8 of 28	NP_001154824.1	Q12791-1
KCNMA1	NM_001437422.1		c.1255G>A	p.Gly419Arg	missense	Exon 9 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.1123G>A	p.Gly375Arg	missense	Exon 8 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.1123G>A	p.Gly375Arg	missense	Exon 8 of 28	ENSP00000286628.8	Q12791-1
KCNMA1	ENST00000626620.3	TSL:1	c.1123G>A	p.Gly375Arg	missense	Exon 8 of 28	ENSP00000485867.1	Q12791-2
KCNMA1	ENST00000639406.1	TSL:1	c.1123G>A	p.Gly375Arg	missense	Exon 8 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Liang-Wang syndrome (2)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.97

Sift

Uncertain

0.016

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.89

MutPred

0.79

Gain of methylation at G375 (P = 0.0053)

MVP

0.98

MPC

2.5

ClinPred

1.0

GERP RS

5.5

Varity_R

0.93

gMVP

0.99

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over