chr10-77637586-TCCG-T

Variant names:

• chr10-77637586-TCCG-T
• rs760628050
• NM_001161352.2:c.54_56delCGG

Variant summary

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

The NM_001161352.2(KCNMA1):​c.54_56delCGG​(p.Gly19del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000317 in 1,515,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G18G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	NP_001154824.1
	KCNMA1	NM_001437422.1		c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	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.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 28	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.54_56delCGG	p.Gly19del	disruptive_inframe_deletion	Exon 1 of 29	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.0000927 AC: 14 AN: 151106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000887

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00146 AC: 167 AN: 114424 AF XY: 0.00148

Gnomad AFR exome AF: 0.00249

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00117

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000873

GnomAD4 exome AF: 0.000342 AC: 466 AN: 1364006 Hom.: 0 AF XY: 0.000346 AC XY: 233 AN XY: 672650

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000620 AC: 19 AN: 30658

American (AMR) AF: 0.000905 AC: 31 AN: 34256

Ashkenazi Jewish (ASJ) AF: 0.000653 AC: 16 AN: 24520

East Asian (EAS) AF: 0.000315 AC: 11 AN: 34954

South Asian (SAS) AF: 0.000519 AC: 40 AN: 77070

European-Finnish (FIN) AF: 0.000410 AC: 15 AN: 36584

Middle Eastern (MID) AF: 0.000401 AC: 2 AN: 4986

European-Non Finnish (NFE) AF: 0.000297 AC: 316 AN: 1064088

Other (OTH) AF: 0.000281 AC: 16 AN: 56890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000926 AC: 14 AN: 151210 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73876

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

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10514

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

European-Non Finnish (NFE) AF: 0.0000887 AC: 6 AN: 67648

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

Alfa AF: 0.00393 Hom.: 0

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		5.6
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs760628050; hg19: chr10-79397344;