10-77637586-TCCGCCGCCGCCGCCG-TCCGCCGCCGCCGCCGCCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_001161352.2(KCNMA1):c.56_57insCGG(p.Gly19dup) variant causes a 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 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 5.59

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=4, 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/exons	MANE	UniProt
KCNMA1	NM_001161352.2 linkuse as main transcript	c.56_57insCGG	p.Gly19dup	inframe_insertion	1/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14 linkuse as main transcript	c.56_57insCGG	p.Gly19dup	inframe_insertion	1/28	1	NM_001161352.2	A2	Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

131

AN:

151110

Hom.:

Cov.:

show subpopulations

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:

AN:

114424

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

62920

show subpopulations

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.:

Cov.:

AF XY:

0.000511

AC XY:

346

AN XY:

677458

show subpopulations

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.:

Cov.:

AF XY:

0.000690

AC XY:

AN XY:

73878

show subpopulations

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:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2023	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 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	KCNMA1: BP3, BS2 -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 08, 2022

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

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over