rs863224885

Positions:

• chr10-77110250-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.01

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Activated at more negative voltages. Slower rate of inactivation. Impaired inhibition by HMIMP. No effect on channel inhibition by Iberiotoxin. (size 0) in uniprot entity KCMA1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• 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.
• 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/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1054A>G	p.Thr352Ala	missense_variant	8/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1054A>G	p.Thr352Ala	missense_variant	8/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Dec 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
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	D
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	D
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	D
MutationAssessor	Pathogenic	3.4	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M;M;.;.;.;.;.;M;.;.;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.86	D
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	D
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

Other links and lift over

dbSNP: rs863224885; hg19: chr10-78870008;