10-76953894-A-G

Variant names:

• chr10-76953894-A-G
• rs77280228
• NM_001161352.2:c.2391T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_001161352.2(KCNMA1):​c.2391T>C​(p.Asp797Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,614,024 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (74 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (61 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.279
• Publications: 2 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.191).
• BP6: Variant 10-76953894-A-G is Benign according to our data. Variant chr10-76953894-A-G is described in ClinVar as Benign. ClinVar VariationId is 129323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.279 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.2391T>C	p.Asp797Asp	synonymous	Exon 21 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.2349T>C	p.Asp783Asp	synonymous	Exon 21 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2217T>C	p.Asp739Asp	synonymous	Exon 20 of 28	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.2391T>C	p.Asp797Asp	synonymous	Exon 21 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.2217T>C	p.Asp739Asp	synonymous	Exon 20 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.2226T>C	p.Asp742Asp	synonymous	Exon 21 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2427 AN: 152134 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00410 AC: 1030 AN: 251376 AF XY: 0.00274

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00162 AC: 2371 AN: 1461772 Hom.: 61 Cov.: 32 AF XY: 0.00141 AC XY: 1025 AN XY: 727188

African (AFR) AF: 0.0581 AC: 1945 AN: 33472

American (AMR) AF: 0.00295 AC: 132 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111916

Other (OTH) AF: 0.00351 AC: 212 AN: 60392

GnomAD4 genome AF: 0.0161 AC: 2445 AN: 152252 Hom.: 74 Cov.: 32 AF XY: 0.0161 AC XY: 1197 AN XY: 74446

African (AFR) AF: 0.0547 AC: 2273 AN: 41530

American (AMR) AF: 0.00811 AC: 124 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.00726 Hom.: 16

Bravo AF: 0.0184

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.4
DANN	Benign	0.64
PhyloP100		0.28
Mutation Taster		=99/1	polymorphism (auto)

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: rs77280228; hg19: chr10-78713652;