NM_001161352.2:c.45_55delCGGCGGCGGCG

Variant names:

• chr10-77637587-CCGCCGCCGCCG-C
• NM_001161352.2:c.45_55delCGGCGGCGGCG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001161352.2(KCNMA1):​c.45_55delCGGCGGCGGCG​(p.Gly16ArgfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNMA1 NM_001161352.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• generalized epilepsy-paroxysmal dyskinesia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.45_55delCGGCGGCGGCG	p.Gly16ArgfsTer5	frameshift	Exon 1 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-79397345;