Genetic Variant NM_001161352.2:c.1054A>G (chr10-77110250-T-C) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_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

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the KCNMA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.0622 (above the threshold of 3.09). Trascript score misZ: 6.5162 (above the threshold of 3.09). GenCC associations: The gene is linked to cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.

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 id is 216948.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.1054A>G	p.Thr352Ala	missense_variant	Exon 8 of 28	ENST00000286628.14	NP_001154824.1	Q12791-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 link	c.1054A>G	p.Thr352Ala	missense_variant	Exon 8 of 28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome

Pathogenic:1

Dec 03, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

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

Pathogenic

0.91

MetaRNN

Pathogenic

0.93

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

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M;M;.;.;.;.;.;M;.;.;.;M;M;M;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.3

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

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0, 1.0, 1.0

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

Vest4

0.92, 0.95, 0.91, 0.96, 0.91, 0.82

MutPred

0.67

.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;Loss of glycosylation at T352 (P = 0.0615);.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;.;.;.;.;.;Loss of glycosylation at T352 (P = 0.0615);.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;.;.;Loss of glycosylation at T352 (P = 0.0615);.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);Loss of glycosylation at T352 (P = 0.0615);.;.;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

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