chr10-77637586-TCCG-T

Variant names:

• chr10-77637586-TCCG-T
• rs760628050
• NM_001161352.2:c.54_56delCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001161352.2(KCNMA1):​c.54_56delCGG​(p.Gly19del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000317 in 1,515,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G18G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

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]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000342 (466/1364006) while in subpopulation AMR AF = 0.000905 (31/34256). AF 95% confidence interval is 0.000655. There are 0 homozygotes in GnomAdExome4. There are 233 alleles in the male GnomAdExome4 subpopulation. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.0000927 AC: 14 AN: 151106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000887

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00146 AC: 167 AN: 114424 AF XY: 0.00148

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00117

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000873

GnomAD4 exome AF: 0.000342 AC: 466 AN: 1364006 Hom.: 0 AF XY: 0.000346 AC XY: 233 AN XY: 672650

Gnomad4 AFR exome AF: 0.000620 AC: 19 AN: 30658

Gnomad4 AMR exome AF: 0.000905 AC: 31 AN: 34256

Gnomad4 ASJ exome AF: 0.000653 AC: 16 AN: 24520

Gnomad4 EAS exome AF: 0.000315 AC: 11 AN: 34954

Gnomad4 SAS exome AF: 0.000519 AC: 40 AN: 77070

Gnomad4 FIN exome AF: 0.000410 AC: 15 AN: 36584

Gnomad4 NFE exome AF: 0.000297 AC: 316 AN: 1064088

Gnomad4 Remaining exome AF: 0.000281 AC: 16 AN: 56890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000926 AC: 14 AN: 151210 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73876

Gnomad4 AFR AF: 0.000170 AC: 0.000169738 AN: 0.000169738

Gnomad4 AMR AF: 0.0000656 AC: 0.000065634 AN: 0.000065634

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000887 AC: 0.0000886944 AN: 0.0000886944

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00393 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.54_56del, results in the deletion of 1 amino acid(s) of the KCNMA1 protein (p.Gly20del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNMA1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=69/31	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

Publications

LitVar

Other links and lift over

dbSNP: rs760628050; hg19: chr10-79397344;