rs142770262

chr10-76949303-C-Achr10-76949303-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001161352.2(KCNMA1):c.2548G>T(p.Val850Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. V850I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.02

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]

LOC124902466 (HGNC:):

KCNMA1-AS1 (HGNC:51213): (KCNMA1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNMA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.37441996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.2548G>T	p.Val850Phe	missense_variant	22/28	ENST00000286628.14
LOC124902466	XR_007062207.1	n.718C>A		non_coding_transcript_exon_variant	3/3
KCNMA1-AS1	NR_120655.1	n.458-28307C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.2548G>T	p.Val850Phe	missense_variant	22/28	1	NM_001161352.2	A2
KCNMA1-AS1	ENST00000458661.6	n.426-28307C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.070	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	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	0.0089	T
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.036	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.71, 0.19, 0.22, 0.050	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;B;B;.;.;.;.;.;.;P;B;.;.;B;.;.;.
Vest4		0.68, 0.70, 0.68, 0.70, 0.61, 0.81
MutPred		0.33		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.85
MPC		1.9
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.79

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: rs142770262; hg19: chr10-78709061;