10-77637586-TCCGCCGCCGCCGCCG-TCCGCCGCCGCCGCCGCCG

Variant names:

• chr10-77637586-T-TCCG
• rs760628050
• NM_001161352.2:c.54_56dupCGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001161352.2(KCNMA1):​c.54_56dupCGG​(p.Gly19dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000563 in 1,524,852 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4 O: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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 10-77637586-T-TCCG is Benign according to our data. Variant chr10-77637586-T-TCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193225.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, not_provided=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000873 (132/151214) while in subpopulation AMR AF= 0.00203 (31/15238). AF 95% confidence interval is 0.00147. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.54_56dupCGG	p.Gly19dup	disruptive_inframe_insertion	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_56dupCGG	p.Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 131 AN: 151110 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.000724

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000655 AC: 75 AN: 114424 Hom.: 0 AF XY: 0.000604 AC XY: 38 AN XY: 62920

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.00167

Gnomad EAS exome AF: 0.000817

Gnomad SAS exome AF: 0.0000510

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.000529 AC: 726 AN: 1373638 Hom.: 0 Cov.: 31 AF XY: 0.000511 AC XY: 346 AN XY: 677458

Gnomad4 AFR exome AF: 0.00100

Gnomad4 AMR exome AF: 0.000980

Gnomad4 ASJ exome AF: 0.00198

Gnomad4 EAS exome AF: 0.000710

Gnomad4 SAS exome AF: 0.000410

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.000943

GnomAD4 genome AF: 0.000873 AC: 132 AN: 151214 Hom.: 1 Cov.: 32 AF XY: 0.000690 AC XY: 51 AN XY: 73878

Gnomad4 AFR AF: 0.000946

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00203

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000724

Gnomad4 OTH AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Apr 28, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Feb 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame duplication of 1 amino acid in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNMA1: BP3, BS2 -

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.54_56dup, results in the insertion of 1 amino acid(s) of the KCNMA1 protein (p.Gly20dup), 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: 193225). 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. -

Inborn genetic diseases Benign:1

Mar 31, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

KCNMA1-related disorder Benign:1

Sep 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Infantile epileptic dyskinetic encephalopathy;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

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;