rs767576877

chr10-77403933-C-Gchr10-77403933-C-T

Variant summary

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

The NM_001161352.2(KCNMA1):c.469G>C(p.Gly157Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G157S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 where missense usually causes diseases, KCNMA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.469G>C	p.Gly157Arg	missense_variant	2/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.469G>C	p.Gly157Arg	missense_variant	2/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCNMA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 157 of the KCNMA1 protein (p.Gly157Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.055	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.56
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
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.68	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	-0.66	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.010	D;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;T;.;.;.;.
Polyphen		0.99, 1.0, 1.0, 1.0	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;.;.;.;D;.;.;D;.;.;.;.
Vest4		0.94, 0.96, 0.94, 0.95, 0.96, 0.96
MutPred		0.43		.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;.;.;.;.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);Gain of MoRF binding (P = 0.0091);.;Gain of MoRF binding (P = 0.0091);
MVP		0.85
MPC		2.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.97

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: rs767576877; hg19: chr10-79163691;