rs540783

Variant names:

• chr10-77317955-C-T
• rs540783
• NM_001161352.2:c.541-66699G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001161352.2(KCNMA1):​c.541-66699G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,110 control chromosomes in the GnomAD database, including 3,510 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3510 hom., cov: 32)
• Consequence: KCNMA1 NM_001161352.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.541-66699G>A		intron_variant	Intron 2 of 27	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.541-66699G>A		intron_variant	Intron 2 of 27	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31458 AN: 151992 Hom.: 3503 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0147

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.224

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.207 AC: 31495 AN: 152110 Hom.: 3510 Cov.: 32 AF XY: 0.208 AC XY: 15441 AN XY: 74326

African (AFR) AF: 0.179 AC: 7415 AN: 41502

American (AMR) AF: 0.263 AC: 4024 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 511 AN: 3468

East Asian (EAS) AF: 0.0147 AC: 76 AN: 5172

South Asian (SAS) AF: 0.152 AC: 730 AN: 4816

European-Finnish (FIN) AF: 0.262 AC: 2776 AN: 10582

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 14995 AN: 67980

Other (OTH) AF: 0.226 AC: 478 AN: 2114

Alfa AF: 0.211 Hom.: 1769

Bravo AF: 0.207

Asia WGS AF: 0.0960 AC: 332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.8
DANN	Benign	0.70
PhyloP100		0.13
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: rs540783; hg19: chr10-79077713;