rs754606765

Positions:

chr10-77637469-CGAGGAGGAAGAG-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001161352.2(KCNMA1):c.162_173delCTCTTCCTCCTC(p.Ser55_Ser58del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00176 in 1,610,310 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 6 hom. )

Consequence

KCNMA1
NM_001161352.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 3.85

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:

KCNMA1 (HGNC:):

KCNMA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 10-77637469-CGAGGAGGAAGAG-C is Benign according to our data. Variant chr10-77637469-CGAGGAGGAAGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193230.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, not_provided=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00187 (283/151572) while in subpopulation NFE AF= 0.00166 (113/67882). AF 95% confidence interval is 0.00142. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 linkuse as main transcript	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	1/28	ENST00000286628.14	NP_001154824.1	Q12791-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 linkuse as main transcript	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	1/28	1	NM_001161352.2	ENSP00000286628.8		Q12791-1

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

283

AN:

151456

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000438

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000627

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00177

AC:

431

AN:

244132

Hom.:

AF XY:

0.00175

AC XY:

232

AN XY:

132216

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.000499

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000437

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.00175

AC:

2548

AN:

1458738

Hom.:

AF XY:

0.00175

AC XY:

1272

AN XY:

725334

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000540

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000537

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.00160

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.00187

AC:

283

AN:

151572

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

168

AN XY:

74014

show subpopulations

Gnomad4 AFR

AF:

0.000436

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000628

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.00166

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000812

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	KCNMA1: BS1 -

Generalized epilepsy-paroxysmal dyskinesia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

This variant, c.162_173del, results in the deletion of 4 amino acid(s) of the KCNMA1 protein (p.Ser57_Ser60del), 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: 193230). 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 19, 2016

- -

KCNMA1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

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). -

Cerebellar atrophy, developmental delay, and seizures;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 01-29-2021 by Lab 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