chr6-42929619-TTGCTGCTGC-T

Variant names:

• chr6-42929619-TTGCTGCTGC-T
• rs570105218
• NM_006586.5:c.68_76delTGCTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS1

The NM_006586.5(CNPY3):​c.68_76delTGCTGCTGC​(p.Leu23_Leu25del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000904 in 1,560,578 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.877
• Publications: 3 publications found

Genes affected

CNPY3 (HGNC:11968): (canopy FGF signaling regulator 3) This gene encodes a protein that binds members of the toll-like receptor protein family and functions as a chaperone to aid in folding and export of these proteins. Alternative splicing results in multiple transcript variants. Naturally occuring readthrough transcription occurs between this locus and the downstream GNMT (glycine N-methyltransferase) gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

CNPY3 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 60

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006586.5
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000118 (18/152066) while in subpopulation SAS AF = 0.000414 (2/4826). AF 95% confidence interval is 0.0000955. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006586.5. 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
	CNPY3	NM_006586.5	MANE Select	c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 5	NP_001305786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNPY3	ENST00000372836.5	TSL:1 MANE Select	c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.68_76delTGCTGCTGC	p.Leu23_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000264 AC: 34 AN: 128598 AF XY: 0.000330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000631

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000271

GnomAD4 exome AF: 0.0000873 AC: 123 AN: 1408512 Hom.: 0 AF XY: 0.0000991 AC XY: 69 AN XY: 696212

African (AFR) AF: 0.000248 AC: 8 AN: 32322

American (AMR) AF: 0.000518 AC: 19 AN: 36694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25260

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36984

South Asian (SAS) AF: 0.000410 AC: 33 AN: 80482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.0000507 AC: 55 AN: 1085232

Other (OTH) AF: 0.000120 AC: 7 AN: 58418

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74326

African (AFR) AF: 0.000193 AC: 8 AN: 41526

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67918

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.88
Mutation Taster		=118/82	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs570105218; hg19: chr6-42897357;