chr10-76885309-G-A

Variant names:

• chr10-76885309-G-A
• rs7073015
• NM_001161352.2:c.*1957C>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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• 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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.*1957C>T		3_prime_UTR	Exon 28 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.*1957C>T		3_prime_UTR	Exon 28 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.*1957C>T		3_prime_UTR	Exon 28 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.*1957C>T		3_prime_UTR	Exon 28 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000286627.10	TSL:1	c.*1957C>T		3_prime_UTR	Exon 27 of 27	ENSP00000286627.5	Q12791-5
	KCNMA1	ENST00000640807.1	TSL:1	c.3362+1982C>T		intron	N/A	ENSP00000491555.1	D5MRH1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Generalized epilepsy-paroxysmal dyskinesia syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;