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: 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1361C>T	p.Ala454Val	missense_variant	Exon 11 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1361C>T	p.Ala454Val	missense_variant	Exon 11 of 28	1	NM_001161352.2	ENSP00000286628.8

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 v4.3

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;.;.;.
PhyloP100		10
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
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;