rs886039469

chr10-76891709-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_001161352.2(KCNMA1):c.3158A>G(p.Asn1053Ser) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.67

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

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KCNMA1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 10-76891709-T-C is Pathogenic according to our data. Variant chr10-76891709-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 265313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-76891709-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.3158A>G	p.Asn1053Ser	missense_variant	26/28	ENST00000286628.14
KCNMA1-AS1	NR_120655.1	n.238+3428T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.3158A>G	p.Asn1053Ser	missense_variant	26/28	1	NM_001161352.2	A2
KCNMA1-AS1	ENST00000458661.6	n.206+3428T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 2017	- -
Likely pathogenic, no assertion criteria provided	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Sep 08, 2002	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 995 of the KCNMA1 protein (p.Asn995Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epilepsy and/or paroxysomal dyskinesia (PMID: 26195193, 29330545; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as c.3158A>G (p.Asn1053Ser). ClinVar contains an entry for this variant (Variation ID: 265313). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNMA1 protein function. Experimental studies have shown that this missense change affects KCNMA1 function (PMID: 29330545). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Oct 05, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	Published functional studies demonstrate that N995S results in a gain-of-function with markedly increased macroscopic potassium current (Li et al., 2018; Moldenhauer et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as N1053S using alternate nomenclature; This variant is associated with the following publications: (PMID: 32132200, 32655623, 26195193, 29330545, 30525188, 31152168, 31851553, 32633875, 33043086, 33767182) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	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	0.48	D
MetaRNN	Pathogenic	0.80	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	0.78	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0, 1.0, 0.99, 0.99	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;.;.;.;.;.;D;D;.;.;D;.;.;.
Vest4		0.86, 0.83, 0.76, 0.81, 0.65, 0.67
MutPred		0.35		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.1039);Loss of stability (P = 0.1039);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.1039);.;.;.;Loss of stability (P = 0.1039);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.84
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.68
gMVP		0.99

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: rs886039469; hg19: chr10-78651467;