10-76886778-G-T

Variant names:

• chr10-76886778-G-T
• rs2116830
• NM_001161352.2:c.*488C>A

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.*488C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,025,966 control chromosomes in the GnomAD database, including 18,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1789 hom., cov: 33)
  • Exomes 𝑓: 0.19 (16587 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.891
• Publications: 39 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=-0.68).
• BP6: Variant 10-76886778-G-T is Benign according to our data. Variant chr10-76886778-G-T is described in ClinVar as Benign. ClinVar VariationId is 300951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

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.*488C>A		3_prime_UTR	Exon 28 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.*488C>A		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*488C>A		3_prime_UTR	Exon 28 of 28	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.*488C>A		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8
	KCNMA1	ENST00000639406.1	TSL:1	c.*488C>A		3_prime_UTR	Exon 29 of 29	ENSP00000491732.1
	KCNMA1	ENST00000286627.10	TSL:1	c.*488C>A		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20654 AN: 152050 Hom.: 1789 Cov.: 33

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.191 AC: 166525 AN: 873796 Hom.: 16587 Cov.: 32 AF XY: 0.190 AC XY: 77354 AN XY: 406118

African (AFR) AF: 0.0370 AC: 616 AN: 16650

American (AMR) AF: 0.122 AC: 537 AN: 4412

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 834 AN: 5976

East Asian (EAS) AF: 0.000626 AC: 4 AN: 6394

South Asian (SAS) AF: 0.0425 AC: 944 AN: 22226

European-Finnish (FIN) AF: 0.133 AC: 229 AN: 1722

Middle Eastern (MID) AF: 0.122 AC: 211 AN: 1734

European-Non Finnish (NFE) AF: 0.201 AC: 158249 AN: 785422

Other (OTH) AF: 0.167 AC: 4901 AN: 29260

GnomAD4 genome AF: 0.136 AC: 20646 AN: 152170 Hom.: 1789 Cov.: 33 AF XY: 0.131 AC XY: 9742 AN XY: 74392

African (AFR) AF: 0.0524 AC: 2174 AN: 41528

American (AMR) AF: 0.155 AC: 2366 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5170

South Asian (SAS) AF: 0.0436 AC: 210 AN: 4818

European-Finnish (FIN) AF: 0.149 AC: 1580 AN: 10578

Middle Eastern (MID) AF: 0.186 AC: 54 AN: 290

European-Non Finnish (NFE) AF: 0.195 AC: 13287 AN: 67998

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.169 Hom.: 7670

Bravo AF: 0.134

Asia WGS AF: 0.0280 AC: 99 AN: 3478

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 13, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.7
DANN	Benign	0.51
PhyloP100		0.89
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: rs2116830; hg19: chr10-78646536;