rs1397483743

Variant names:

• chr10-77108523-C-A
• NM_001161352.2:c.1181G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-77108523-C-A
• chr10-77108523-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001161352.2(KCNMA1):​c.1181G>T​(p.Arg394Leu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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 Uncertain_significance. Variant got 5 ACMG points.

• 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, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1181G>T	p.Arg394Leu	missense_variant	Exon 9 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1181G>T	p.Arg394Leu	missense_variant	Exon 9 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 29, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	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	Uncertain	0.20	D
MetaRNN	Pathogenic	0.88	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	Uncertain	0.51	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M;M;.;.;.;.;.;M;.;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0090	D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen		0.90, 1.0, 0.97, 1.0, 0.99, 0.99	.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;.;.;.;.;D;D;.;D;.;.;.;.;.
Vest4		0.83, 0.85, 0.84, 0.83, 0.81, 0.84, 0.64, 0.73
MutPred		0.62		.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;.;.;.;.;.;Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;.;.;Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;.;Loss of disorder (P = 0.0411);
MVP		0.94
MPC		2.6
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-78868281;