rs78670694

Variant names:

• chr10-77019006-C-T
• rs78670694
• NM_001161352.2:c.2015+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):​c.2015+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,514,648 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (23 hom.)
• Consequence: KCNMA1 NM_001161352.2 splice_region, intron
• Scores: Splicing: ADA: 0.00009509
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.414
• 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: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 10-77019006-C-T is Benign according to our data. Variant chr10-77019006-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00137 (208/152282) while in subpopulation EAS AF = 0.0286 (148/5178). AF 95% confidence interval is 0.0248. There are 4 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.2015+7G>A		splice_region intron	N/A	NP_001154824.1
	KCNMA1	NM_001437422.1		c.2147+7G>A		splice_region intron	N/A	NP_001424351.1
	KCNMA1	NM_001161353.2		c.2015+7G>A		splice_region intron	N/A	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.2015+7G>A		splice_region intron	N/A	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.2015+7G>A		splice_region intron	N/A	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.2015+7G>A		splice_region intron	N/A	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152164 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00255 AC: 639 AN: 250276 AF XY: 0.00250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0247

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00129 AC: 1762 AN: 1362366 Hom.: 23 Cov.: 22 AF XY: 0.00135 AC XY: 924 AN XY: 683806

African (AFR) AF: 0.00 AC: 0 AN: 31396

American (AMR) AF: 0.0000224 AC: 1 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.000548 AC: 14 AN: 25544

East Asian (EAS) AF: 0.0289 AC: 1128 AN: 39082

South Asian (SAS) AF: 0.00269 AC: 226 AN: 84128

European-Finnish (FIN) AF: 0.00156 AC: 83 AN: 53300

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5616

European-Non Finnish (NFE) AF: 0.000214 AC: 219 AN: 1021734

Other (OTH) AF: 0.00158 AC: 90 AN: 56982

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152282 Hom.: 4 Cov.: 33 AF XY: 0.00156 AC XY: 116 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0286 AC: 148 AN: 5178

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00147

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000297

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	-	2	not specified (2)
-	-	1	KCNMA1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		-0.41
PromoterAI		0.0090	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000095
dbscSNV1_RF	Benign	0.0
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: rs78670694; hg19: chr10-78778764; COSMIC: COSV54294368;