rs200420124

Variant names:

• chr10-77637461-A-G
• rs200420124
• NM_001161352.2:c.182T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001161352.2(KCNMA1):​c.182T>C​(p.Val61Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000595 in 1,612,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.45
• 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 Gene-Disease associations (from GenCC):

• generalized epilepsy-paroxysmal dyskinesia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07896823).

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.182T>C	p.Val61Ala	missense	Exon 1 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.182T>C	p.Val61Ala	missense	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.182T>C	p.Val61Ala	missense	Exon 1 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.182T>C	p.Val61Ala	missense	Exon 1 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.182T>C	p.Val61Ala	missense	Exon 1 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.182T>C	p.Val61Ala	missense	Exon 1 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152020 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000811 AC: 20 AN: 246588 AF XY: 0.0000674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1460208 Hom.: 0 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 726166

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.000269 AC: 12 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 33 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111232

Other (OTH) AF: 0.0000829 AC: 5 AN: 60340

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152020 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	1	-	Cerebellar atrophy, developmental delay, and seizures;C5231421:Epilepsy, idiopathic generalized, susceptibility to, 16;C5231479:Liang-Wang syndrome;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0085	T
Eigen	Benign	0.087
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.069
Sift	Benign	0.036	D
Sift4G	Benign	0.30	T
Polyphen		0.96	D
Vest4		0.32
MutPred		0.14		Loss of stability (P = 0.0165)
MVP		0.48
ClinPred		0.10	T
GERP RS		2.9
PromoterAI		0.054	Neutral
Varity_R		0.063
gMVP		0.51
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200420124; hg19: chr10-79397219;