10-77637612-TGCCGCCGCCGCC-TGCCGCC

Variant names:

• chr10-77637612-TGCCGCC-T
• rs750804948
• NM_001161352.2:c.25_30delGGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001161352.2(KCNMA1):​c.25_30delGGCGGC​(p.Gly9_Gly10del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNMA1 NM_001161352.2 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44
• 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: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• Liang-Wang syndrome

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001161352.2

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.25_30delGGCGGC	p.Gly9_Gly10del	conservative_inframe_deletion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1371672 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 676310

African (AFR) AF: 0.00 AC: 0 AN: 30826

American (AMR) AF: 0.00 AC: 0 AN: 34538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24544

East Asian (EAS) AF: 0.00 AC: 0 AN: 35224

South Asian (SAS) AF: 0.00 AC: 0 AN: 77876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071382

Other (OTH) AF: 0.00 AC: 0 AN: 57196

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=135/65	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs750804948; hg19: chr10-79397370;