Genetic Variant NM_001161352.2:c.1054A>G (chr10-77110250-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_001161352.2(KCNMA1):c.1054A>G(p.Thr352Ala) 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 (★). Synonymous variant affecting the same amino acid position (i.e. T352T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNMA1
NM_001161352.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.01

Publications

4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
Liang-Wang syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
cerebellar atrophy, developmental delay, and seizures
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

KCNMA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001161352.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 10-77110250-T-C is Pathogenic according to our data. Variant chr10-77110250-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 216948.Status of the report is criteria_provided_single_submitter, 1 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.1054A>G	p.Thr352Ala	missense	Exon 8 of 28	NP_001154824.1	Q12791-1
KCNMA1	NM_001437422.1		c.1186A>G	p.Thr396Ala	missense	Exon 9 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.1054A>G	p.Thr352Ala	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.1054A>G	p.Thr352Ala	missense	Exon 8 of 28	ENSP00000286628.8	Q12791-1
KCNMA1	ENST00000626620.3	TSL:1	c.1054A>G	p.Thr352Ala	missense	Exon 8 of 28	ENSP00000485867.1	Q12791-2
KCNMA1	ENST00000639406.1	TSL:1	c.1054A>G	p.Thr352Ala	missense	Exon 8 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

PhyloP100

8.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.92

MutPred

0.67

Loss of glycosylation at T352 (P = 0.0615)

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

5.5

Varity_R

0.81

gMVP

0.99

Mutation Taster

=0/100

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

Computational scores

Splicing

Publications

Other links and lift over