NM_001161352.2:c.*2183C>T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*2183C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628	c.*2183C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8

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

Gnomad4 AFR exome AF: 0.000608

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00354

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

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.000854

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0200

Gnomad4 FIN AF: 0.000868

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00286

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs201067003; hg19: chr10-78644841;