rs1554966197

Variant names:

• chr10-76944851-C-T
• rs1554966197
• NM_001161352.2:c.2824G>A
• KCNMA1 p.Glu942Lys

Your query was ambiguous. Multiple possible variants found:

• chr10-76944851-C-T
• chr10-76944851-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001161352.2(KCNMA1):​c.2824G>A​(p.Glu942Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E942E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.81
• Publications: 1 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)

LOC124902466 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-76944851-C-T is Pathogenic according to our data. Variant chr10-76944851-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 437870.Status of the report is no_assertion_criteria_provided, 0 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.2824G>A	p.Glu942Lys	missense	Exon 23 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.2782G>A	p.Glu928Lys	missense	Exon 23 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2773G>A	p.Glu925Lys	missense	Exon 23 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.2824G>A	p.Glu942Lys	missense	Exon 23 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.2773G>A	p.Glu925Lys	missense	Exon 23 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.2659G>A	p.Glu887Lys	missense	Exon 23 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.56
Sift	Benign	0.053	T
Sift4G	Uncertain	0.0020	D
Varity_R		0.94
gMVP		0.89
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1554966197;

hg19: chr10-78704609;