chr10-77637586-TCCGCCG-T

Variant names:

• chr10-77637586-TCCGCCG-T
• rs760628050
• NM_001161352.2:c.51_56delCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001161352.2(KCNMA1):​c.51_56delCGGCGG​(p.Gly18_Gly19del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000109 in 1,373,576 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. G17G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.59
• Publications: 0 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001161352.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.51_56delCGGCGG	p.Gly18_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.51_56delCGGCGG	p.Gly18_Gly19del	disruptive_inframe_deletion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000350 AC: 4 AN: 114424 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 15 AN: 1373576 Hom.: 0 AF XY: 0.0000118 AC XY: 8 AN XY: 677430

African (AFR) AF: 0.0000323 AC: 1 AN: 30916

American (AMR) AF: 0.00 AC: 0 AN: 34692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24708

East Asian (EAS) AF: 0.00 AC: 0 AN: 35200

South Asian (SAS) AF: 0.0000641 AC: 5 AN: 77958

European-Finnish (FIN) AF: 0.0000544 AC: 2 AN: 36756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5006

European-Non Finnish (NFE) AF: 0.00000654 AC: 7 AN: 1071060

Other (OTH) AF: 0.00 AC: 0 AN: 57280

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Dec 08, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.51_56del, results in the deletion of 2 amino acid(s) of the KCNMA1 protein (p.Gly19_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. ClinVar contains an entry for this variant (Variation ID: 2433010). 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
PhyloP100		5.6
Mutation Taster		=139/61	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760628050; hg19: chr10-79397344;