chr10-77637586-T-TCCGCCGCCG

Variant names:

• chr10-77637586-T-TCCGCCGCCG
• rs760628050
• NM_001161352.2:c.48_56dupCGGCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001161352.2(KCNMA1):​c.48_56dupCGGCGGCGG​(p.Gly17_Gly19dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000374 in 1,524,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.59
• 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: Likely_benign. The variant received -1 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	NP_001154825.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.48_56dupCGGCGGCGG	p.Gly17_Gly19dup	disruptive_inframe_insertion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.0000860 AC: 13 AN: 151112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000739

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000320 AC: 44 AN: 1373660 Hom.: 0 Cov.: 31 AF XY: 0.0000354 AC XY: 24 AN XY: 677468

African (AFR) AF: 0.00 AC: 0 AN: 30918

American (AMR) AF: 0.00 AC: 0 AN: 34692

Ashkenazi Jewish (ASJ) AF: 0.0000405 AC: 1 AN: 24708

East Asian (EAS) AF: 0.00 AC: 0 AN: 35200

South Asian (SAS) AF: 0.00 AC: 0 AN: 77968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5006

European-Non Finnish (NFE) AF: 0.0000373 AC: 40 AN: 1071128

Other (OTH) AF: 0.0000524 AC: 3 AN: 57282

GnomAD4 genome AF: 0.0000860 AC: 13 AN: 151216 Hom.: 0 Cov.: 32 AF XY: 0.0000947 AC XY: 7 AN XY: 73880

African (AFR) AF: 0.000170 AC: 7 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000739 AC: 5 AN: 67648

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs760628050; hg19: chr10-79397344;