chr10-76885083-G-A

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, 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 -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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 AR,AD 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	ENST00000286628.14	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

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

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;