10-76884892-C-CT

Variant names:

• chr10-76884892-C-CT
• rs552322812
• NM_001161352.2:c.*2373dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001161352.2(KCNMA1):​c.*2373dupA variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000964 in 1,381,982 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: KCNMA1 NM_001161352.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.24
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00117 (176/150708) while in subpopulation EAS AF = 0.00857 (44/5136). AF 95% confidence interval is 0.00656. There are 2 homozygotes in GnomAd4. There are 91 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 GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.*2373dupA		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.*2373dupA		3_prime_UTR_variant	Exon 28 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 176 AN: 150596 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00855

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.0000982

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.000962

GnomAD4 exome AF: 0.000939 AC: 1156 AN: 1231274 Hom.: 1 Cov.: 26 AF XY: 0.000949 AC XY: 572 AN XY: 602680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000473 AC: 12 AN: 25386

American (AMR) AF: 0.0109 AC: 186 AN: 17100

Ashkenazi Jewish (ASJ) AF: 0.000554 AC: 11 AN: 19862

East Asian (EAS) AF: 0.0109 AC: 326 AN: 29908

South Asian (SAS) AF: 0.00115 AC: 62 AN: 54148

European-Finnish (FIN) AF: 0.000376 AC: 16 AN: 42544

Middle Eastern (MID) AF: 0.000589 AC: 3 AN: 5090

European-Non Finnish (NFE) AF: 0.000486 AC: 480 AN: 986960

Other (OTH) AF: 0.00119 AC: 60 AN: 50276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00117 AC: 176 AN: 150708 Hom.: 2 Cov.: 30 AF XY: 0.00124 AC XY: 91 AN XY: 73538

African (AFR) AF: 0.000462 AC: 19 AN: 41132

American (AMR) AF: 0.00616 AC: 93 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00857 AC: 44 AN: 5136

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4726

European-Finnish (FIN) AF: 0.0000982 AC: 1 AN: 10188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67664

Other (OTH) AF: 0.000951 AC: 2 AN: 2102

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
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: rs552322812; hg19: chr10-78644650; COSMIC: COSV99695092; COSMIC: COSV99695092;