rs780558929

chr10-77637627-C-CGCT

Variant summary

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

The NM_001161352.2(KCNMA1):c.15_16insAGC(p.Gly5_Gly6insSer) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,523,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G5G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.25

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 10-77637627-C-CGCT is Benign according to our data. Variant chr10-77637627-C-CGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 300975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000926 (14/151228) while in subpopulation EAS AF= 0.00236 (12/5084). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.15_16insAGC	p.Gly5_Gly6insSer	inframe_insertion	1/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.15_16insAGC	p.Gly5_Gly6insSer	inframe_insertion	1/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000926 AC: 14 AN: 151228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00236

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000440 AC: 54 AN: 122676 Hom.: 0 AF XY: 0.000462 AC XY: 31 AN XY: 67130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000856

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00495

Gnomad SAS exome AF: 0.0000483

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000262

GnomAD4 exome AF: 0.0000692 AC: 95 AN: 1372060 Hom.: 0 Cov.: 33 AF XY: 0.0000695 AC XY: 47 AN XY: 676418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00147

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000699

GnomAD4 genome AF: 0.0000926 AC: 14 AN: 151228 Hom.: 0 Cov.: 32 AF XY: 0.0000542 AC XY: 4 AN XY: 73814

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00236

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.00233 AC: 8 AN: 3454

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This variant, c.15_16insAGC, results in the insertion of 1 amino acid(s) of the KCNMA1 protein (p.Gly5_Gly6insSer), 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 been observed in individual(s) with drug resistant focal seizures (PMID: 29933521). ClinVar contains an entry for this variant (Variation ID: 300975). 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 provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	This variant is associated with the following publications: (PMID: 29933521) -

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: rs780558929; hg19: chr10-79397385;