10-76885695-G-A

Variant names:

• chr10-76885695-G-A
• rs10762733
• NM_001161352.2:c.*1571C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001161352.2(KCNMA1):​c.*1571C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 984,658 control chromosomes in the GnomAD database, including 151,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19488 hom., cov: 31)
  • Exomes 𝑓: 0.56 (132450 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.252
• Publications: 7 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=-0.93).
• BP6: Variant 10-76885695-G-A is Benign according to our data. Variant chr10-76885695-G-A is described in ClinVar as [Benign]. Clinvar id is 300933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*1571C>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.*1571C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75009 AN: 151776 Hom.: 19479 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.519

GnomAD4 exome AF: 0.562 AC: 467923 AN: 832764 Hom.: 132450 Cov.: 32 AF XY: 0.562 AC XY: 216310 AN XY: 384588

African (AFR) AF: 0.366 AC: 5783 AN: 15780

American (AMR) AF: 0.354 AC: 347 AN: 980

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 3329 AN: 5152

East Asian (EAS) AF: 0.285 AC: 1033 AN: 3630

South Asian (SAS) AF: 0.381 AC: 6266 AN: 16452

European-Finnish (FIN) AF: 0.623 AC: 172 AN: 276

Middle Eastern (MID) AF: 0.562 AC: 910 AN: 1620

European-Non Finnish (NFE) AF: 0.572 AC: 435538 AN: 761584

Other (OTH) AF: 0.533 AC: 14545 AN: 27290

GnomAD4 genome AF: 0.494 AC: 75032 AN: 151894 Hom.: 19488 Cov.: 31 AF XY: 0.487 AC XY: 36163 AN XY: 74218

African (AFR) AF: 0.382 AC: 15817 AN: 41382

American (AMR) AF: 0.416 AC: 6353 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2229 AN: 3470

East Asian (EAS) AF: 0.300 AC: 1550 AN: 5160

South Asian (SAS) AF: 0.357 AC: 1715 AN: 4798

European-Finnish (FIN) AF: 0.580 AC: 6116 AN: 10546

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39437 AN: 67952

Other (OTH) AF: 0.516 AC: 1089 AN: 2110

Alfa AF: 0.554 Hom.: 27532

Bravo AF: 0.477

Asia WGS AF: 0.314 AC: 1092 AN: 3476

ClinVar

Significance: 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: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.93
CADD	Benign	0.87
DANN	Benign	0.69
PhyloP100		0.25
Mutation Taster		=100/0	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: rs10762733; hg19: chr10-78645453;