rs41281548

Variant names:

• chr10-76884941-A-T
• rs41281548
• NM_001161352.2:c.*2325T>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001161352.2(KCNMA1):​c.*2325T>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 0.00136 in 1,522,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000966 (147/152206) while in subpopulation NFE AF = 0.00168 (114/68026). AF 95% confidence interval is 0.00143. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*2325T>A		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.*2325T>A		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 147 AN: 152088 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000685 AC: 88 AN: 128458 AF XY: 0.000525

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00140 AC: 1921 AN: 1369972 Hom.: 3 Cov.: 30 AF XY: 0.00133 AC XY: 895 AN XY: 674538

African (AFR) AF: 0.000132 AC: 4 AN: 30234

American (AMR) AF: 0.000364 AC: 11 AN: 30214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24096

East Asian (EAS) AF: 0.00 AC: 0 AN: 34754

South Asian (SAS) AF: 0.0000416 AC: 3 AN: 72162

European-Finnish (FIN) AF: 0.000523 AC: 25 AN: 47816

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5580

European-Non Finnish (NFE) AF: 0.00170 AC: 1815 AN: 1068170

Other (OTH) AF: 0.00109 AC: 62 AN: 56946

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152206 Hom.: 0 Cov.: 30 AF XY: 0.000806 AC XY: 60 AN XY: 74414

African (AFR) AF: 0.000433 AC: 18 AN: 41544

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000897 Hom.: 0

Bravo AF: 0.000880

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism

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: rs41281548; hg19: chr10-78644699;