chr10-77086567-G-A

Variant names:

• chr10-77086567-G-A
• rs1057518815
• NM_001161352.2:c.1361C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001161352.2(KCNMA1):​c.1361C>T​(p.Ala454Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A454D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
• Liang-Wang syndrome

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.1361C>T	p.Ala454Val	missense	Exon 11 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.1493C>T	p.Ala498Val	missense	Exon 12 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.1361C>T	p.Ala454Val	missense	Exon 11 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.1361C>T	p.Ala454Val	missense	Exon 11 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.1361C>T	p.Ala454Val	missense	Exon 11 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.1361C>T	p.Ala454Val	missense	Exon 11 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.026	D
Polyphen		0.90	P
Vest4		0.75
MutPred		0.38		Gain of ubiquitination at K457 (P = 0.0913)
MVP		0.65
MPC		1.8
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.81
gMVP		0.91
Mutation Taster		=19/81	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: rs1057518815; hg19: chr10-78846325;