10-76884940-G-T

Variant names:

• chr10-76884940-G-T
• rs199764115
• NM_001161352.2:c.*2326C>A

Variant summary

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

The NM_001161352.2(KCNMA1):​c.*2326C>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0000158 in 1,517,626 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 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15
• Publications: 0 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: Illumina, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• Liang-Wang syndrome

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).

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.*2326C>A		3_prime_UTR	Exon 28 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.*2326C>A		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*2326C>A		3_prime_UTR	Exon 28 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.*2326C>A		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000286627.10	TSL:1	c.*2326C>A		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5	Q12791-5
	KCNMA1	ENST00000640807.1	TSL:1	c.3362+2351C>A		intron	N/A	ENSP00000491555.1	D5MRH1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151654 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000237 AC: 3 AN: 126828 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.000280

GnomAD4 exome AF: 0.0000154 AC: 21 AN: 1365972 Hom.: 0 Cov.: 30 AF XY: 0.0000208 AC XY: 14 AN XY: 672420

African (AFR) AF: 0.00 AC: 0 AN: 30034

American (AMR) AF: 0.00 AC: 0 AN: 29874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23974

East Asian (EAS) AF: 0.00 AC: 0 AN: 34454

South Asian (SAS) AF: 0.0000699 AC: 5 AN: 71494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47738

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5562

European-Non Finnish (NFE) AF: 0.0000113 AC: 12 AN: 1066106

Other (OTH) AF: 0.0000353 AC: 2 AN: 56736

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151654 Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2 AN XY: 74012

African (AFR) AF: 0.00 AC: 0 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.91
PhyloP100		6.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199764115; hg19: chr10-78644698;