rs201067003

Variant names:

• chr10-76885083-G-A
• rs201067003
• NM_001161352.2:c.*2183C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001161352.2(KCNMA1):​c.*2183C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00362 in 1,540,192 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0037 (34 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.85
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 10-76885083-G-A is Benign according to our data. Variant chr10-76885083-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 300924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00245 (372/151654) while in subpopulation SAS AF = 0.02 (96/4806). AF 95% confidence interval is 0.0167. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.*2183C>T		3_prime_UTR	Exon 28 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.*2183C>T		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*2183C>T		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.*2183C>T		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000286627.10	TSL:1	c.*2183C>T		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5	Q12791-5
	KCNMA1	ENST00000640807.1	TSL:1	c.3362+2208C>T		intron	N/A	ENSP00000491555.1	D5MRH1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 373 AN: 151550 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000509

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000855

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0200

Gnomad FIN AF: 0.000868

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00374 AC: 5196 AN: 1388538 Hom.: 34 Cov.: 29 AF XY: 0.00415 AC XY: 2843 AN XY: 684596

African (AFR) AF: 0.000608 AC: 19 AN: 31242

American (AMR) AF: 0.00120 AC: 41 AN: 34288

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 103 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 35376

South Asian (SAS) AF: 0.0173 AC: 1337 AN: 77076

European-Finnish (FIN) AF: 0.00105 AC: 50 AN: 47798

Middle Eastern (MID) AF: 0.0101 AC: 57 AN: 5666

European-Non Finnish (NFE) AF: 0.00315 AC: 3385 AN: 1074528

Other (OTH) AF: 0.00354 AC: 204 AN: 57648

GnomAD4 genome AF: 0.00245 AC: 372 AN: 151654 Hom.: 1 Cov.: 30 AF XY: 0.00248 AC XY: 184 AN XY: 74070

African (AFR) AF: 0.000507 AC: 21 AN: 41408

American (AMR) AF: 0.000854 AC: 13 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.0200 AC: 96 AN: 4806

European-Finnish (FIN) AF: 0.000868 AC: 9 AN: 10366

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 67930

Other (OTH) AF: 0.00286 AC: 6 AN: 2100

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		4.9
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: rs201067003; hg19: chr10-78644841;