rs886039469

Variant names:

• chr10-76891709-T-C
• rs886039469
• NM_001161352.2:c.3158A>G
• KCNMA1 p.Asn1053Ser

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 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 (★★). ClinVar reports functional evidence for this variant: "SCV000322055: Published functional studies demonstrate that N995S results in a gain-of-function with markedly increased macroscopic potassium current (Li et al., 2018" and additional evidence is available in ClinVar.

• 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
• Publications: 34 publications found

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

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322055: 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); SCV000830549: Experimental studies have shown that this missense change affects KCNMA1 function (PMID: 29330545).
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 265313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.3158A>G	p.Asn1053Ser	missense	Exon 26 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.3116A>G	p.Asn1039Ser	missense	Exon 26 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.3107A>G	p.Asn1036Ser	missense	Exon 26 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.3158A>G	p.Asn1053Ser	missense	Exon 26 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.3107A>G	p.Asn1036Ser	missense	Exon 26 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.3074A>G	p.Asn1025Ser	missense	Exon 27 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (5)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.68
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886039469;

hg19: chr10-78651467;