10-77184832-G-C

Variant names:

• chr10-77184832-G-C
• rs1131824
• NM_001161352.2:c.687C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001161352.2(KCNMA1):​c.687C>G​(p.Phe229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F229F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.687C>G	p.Phe229Leu	missense_variant	Exon 4 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.687C>G	p.Phe229Leu	missense_variant	Exon 4 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.078
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.87	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
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.76	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	Benign	-0.80	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L;L;.;.;.;.;.;L;.;.;.;L;L;L;.;.
PhyloP100		1.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.6	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;.;D;.;.;.;.
Polyphen		0.58, 0.019, 0.86, 0.10, 0.84	.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;P;B;.;.;.;.;.;B;P;.;.;P;.;.;.;.
Vest4		0.84, 0.86, 0.83, 0.83, 0.78, 0.83, 0.60, 0.70
MutPred		0.52		.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;.;.;.;.;.;Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;.;.;Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);Loss of methylation at R232 (P = 0.1134);.;Loss of methylation at R232 (P = 0.1134);
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.033	Neutral
Varity_R		0.48
gMVP		0.94
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1131824; hg19: chr10-78944590;