rs754606765

Variant names:

• chr10-77637469-CGAGGAGGAAGAG-C
• rs754606765
• NM_001161352.2:c.162_173delCTCTTCCTCCTC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4 O:1
• Conservation: PhyloP100: 3.85

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 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, Benign=1, Uncertain_significance=1, not_provided=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 rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	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.162_173delCTCTTCCTCCTC	p.Ser55_Ser58del	disruptive_inframe_deletion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 283 AN: 151456 Hom.: 2 Cov.: 32

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.: 3 AF XY: 0.00175 AC XY: 232 AN XY: 132216

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.: 6 AF XY: 0.00175 AC XY: 1272 AN XY: 725334

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.: 2 Cov.: 32 AF XY: 0.00227 AC XY: 168 AN XY: 74014

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.: 0

Bravo AF: 0.000812

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Nov 01, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNMA1: BS1 -

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 19, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KCNMA1-related disorder Benign:1

Feb 05, 2020

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). -

Cerebellar atrophy, developmental delay, and seizures;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 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs754606765; hg19: chr10-79397227;