rs1554829003

Positions:

• chr10-77110181-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001161352.2(KCNMA1):​c.1123G>A​(p.Gly375Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 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, 0.939
• PP5: Variant 10-77110181-C-T is Pathogenic according to our data. Variant chr10-77110181-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521128.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.1123G>A	p.Gly375Arg	missense_variant	8/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1123G>A	p.Gly375Arg	missense_variant	8/28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Liang-Wang syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	Centre of Medical Genetics, University of Antwerp	Nov 16, 2020	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.1123G>A (p.G375R) alteration is located in exon 8 (coding exon 8) of the KCNMA1 gene. This alteration results from a G to A substitution at nucleotide position 1123, causing the glycine (G) at amino acid position 375 to be replaced by an arginine (R). for autosomal dominant KCNMA1-related neurological disorder; however, its clinical significance for autosomal recessive KCNMA1-related neurodevelopmental disorder is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with KCNMA1-related neurodevelopmental movement disorder (Liang, 2019; Rodrigues Bento, 2021; Mameli, 2021; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
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;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	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;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;M;M;.;.;.;.;.;M;.;.;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.6	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.016	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.027	D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen		1.0	.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;.;.;.;.;D;D;.;.;D;.;.;.;.;.
Vest4		0.89, 0.93, 0.89, 0.89, 0.94, 0.88, 0.83
MutPred		0.79		.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;Gain of methylation at G375 (P = 0.0053);.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;.;.;.;.;.;Gain of methylation at G375 (P = 0.0053);.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;.;.;Gain of methylation at G375 (P = 0.0053);.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);Gain of methylation at G375 (P = 0.0053);.;.;Gain of methylation at G375 (P = 0.0053);
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554829003; hg19: chr10-78869939; COSMIC: COSV99695945;