rs7073015

Variant names:

• chr10-76885309-G-A
• rs7073015
• NM_001161352.2:c.*1957C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-76885309-G-A
• chr10-76885309-G-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.*1957C>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 0.786 in 865,032 control chromosomes in the GnomAD database, including 268,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48763 hom., cov: 28)
  • Exomes 𝑓: 0.78 (220093 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.449
• Publications: 9 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=-0.85).
• BP6: Variant 10-76885309-G-A is Benign according to our data. Variant chr10-76885309-G-A is described in ClinVar as [Benign]. Clinvar id is 300927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*1957C>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.*1957C>T		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.804 AC: 119662 AN: 148894 Hom.: 48735 Cov.: 28

Gnomad AFR AF: 0.905

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.732

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.782 AC: 560354 AN: 716114 Hom.: 220093 Cov.: 9 AF XY: 0.783 AC XY: 261077 AN XY: 333562

African (AFR) AF: 0.914 AC: 12206 AN: 13354

American (AMR) AF: 0.651 AC: 591 AN: 908

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 3394 AN: 4480

East Asian (EAS) AF: 0.473 AC: 1566 AN: 3314

South Asian (SAS) AF: 0.610 AC: 8666 AN: 14218

European-Finnish (FIN) AF: 0.891 AC: 230 AN: 258

Middle Eastern (MID) AF: 0.701 AC: 992 AN: 1416

European-Non Finnish (NFE) AF: 0.787 AC: 514938 AN: 654694

Other (OTH) AF: 0.757 AC: 17771 AN: 23472

GnomAD4 genome AF: 0.804 AC: 119707 AN: 148918 Hom.: 48763 Cov.: 28 AF XY: 0.800 AC XY: 58051 AN XY: 72598

African (AFR) AF: 0.905 AC: 36972 AN: 40840

American (AMR) AF: 0.706 AC: 10519 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2636 AN: 3464

East Asian (EAS) AF: 0.499 AC: 2546 AN: 5106

South Asian (SAS) AF: 0.613 AC: 2907 AN: 4744

European-Finnish (FIN) AF: 0.867 AC: 7969 AN: 9196

Middle Eastern (MID) AF: 0.754 AC: 214 AN: 284

European-Non Finnish (NFE) AF: 0.795 AC: 53630 AN: 67426

Other (OTH) AF: 0.767 AC: 1577 AN: 2056

Alfa AF: 0.788 Hom.: 28511

Bravo AF: 0.795

Asia WGS AF: 0.618 AC: 2142 AN: 3468

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.4
DANN	Benign	0.36
PhyloP100		0.45
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: rs7073015; hg19: chr10-78645067; COSMIC: COSV54292767; COSMIC: COSV54292767;