Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001161352.2(KCNMA1):c.3158A>G(p.Asn1053Ser) 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.67

Publications

32 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 links:

KCNMA1-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

KCNMA1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

PP5

Variant 10-76891709-T-C is Pathogenic according to our data. Variant chr10-76891709-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 265313.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
KCNMA1	NM_001161352.2	MANE Select	c.3158A>G	p.Asn1053Ser	missense	Exon 26 of 28	NP_001154824.1
KCNMA1	NM_001437422.1		c.3116A>G	p.Asn1039Ser	missense	Exon 26 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.3107A>G	p.Asn1036Ser	missense	Exon 26 of 28	NP_001154825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.3158A>G	p.Asn1053Ser	missense	Exon 26 of 28	ENSP00000286628.8
KCNMA1	ENST00000626620.3	TSL:1	c.3107A>G	p.Asn1036Ser	missense	Exon 26 of 28	ENSP00000485867.1
KCNMA1	ENST00000639406.1	TSL:1	c.3074A>G	p.Asn1025Ser	missense	Exon 27 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Generalized epilepsy-paroxysmal dyskinesia syndrome (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.8

PhyloP100

7.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.4

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.35

Loss of stability (P = 0.1039)

MVP

0.84

MPC

2.1

ClinPred

0.99

GERP RS

5.5

Varity_R

0.68

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over