rs1397483743

Positions:

• chr10-77108523-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001161352.2(KCNMA1):​c.1181G>A​(p.Arg394His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.54

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1181G>A	p.Arg394His	missense_variant	9/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1181G>A	p.Arg394His	missense_variant	9/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNMA1 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 532942). This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 394 of the KCNMA1 protein (p.Arg394His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	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	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	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	Uncertain	0.61	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M;M;.;.;.;.;.;M;.;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0080	D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen		0.90, 1.0, 0.99, 0.98	.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;.;.;.;.;D;D;.;D;.;.;.;.;.
Vest4		0.69, 0.67, 0.68, 0.68, 0.60, 0.63, 0.47, 0.56
MutPred		0.61		.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;Gain of ubiquitination at K395 (P = 0.0619);.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;.;.;.;.;.;Gain of ubiquitination at K395 (P = 0.0619);.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;.;.;Gain of ubiquitination at K395 (P = 0.0619);.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);Gain of ubiquitination at K395 (P = 0.0619);.;.;Gain of ubiquitination at K395 (P = 0.0619);
MVP		0.94
MPC		2.6
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.67
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1397483743; hg19: chr10-78868281; COSMIC: COSV54251427;