rs863224885

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 (★). 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
• 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]

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 where missense usually causes diseases, KCNMA1
• 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	UniProt
KCNMA1	NM_001161352.2	c.1054A>G	p.Thr352Ala	missense_variant	8/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1054A>G	p.Thr352Ala	missense_variant	8/28	1	NM_001161352.2	A2

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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	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;