rs1057518815

Positions:

• chr10-77086567-G-A
• chr10-77086567-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000286628.14(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 ENST00000286628.14 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 3 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1361C>T	p.Ala454Val	missense_variant	11/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1361C>T	p.Ala454Val	missense_variant	11/28	1	NM_001161352.2	ENSP00000286628	A2

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	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;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	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;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.62	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	-0.45	T
MutationAssessor	Benign	1.9	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;L;L;.;.;.;.;L;.;.;.;L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.026	D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen		0.90, 1.0, 0.88, 1.0, 0.80	.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;P;D;.;.;.;.;D;P;.;.;P;.;.;.;.;.
Vest4		0.75, 0.75, 0.73, 0.73, 0.67, 0.75, 0.56, 0.65
MutPred		0.38		.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;Gain of ubiquitination at K457 (P = 0.0913);.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;.;.;.;.;.;Gain of ubiquitination at K457 (P = 0.0913);.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;.;.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);Gain of ubiquitination at K457 (P = 0.0913);.;.;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

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: rs1057518815; hg19: chr10-78846325;