6-42929619-TTGCTGCTGCTGCTGCTGC-TTGCTGCTGCTGC

Variant names:

• chr6-42929619-TTGCTGC-T
• rs570105218
• NM_006586.5:c.71_76delTGCTGC

Variant summary

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

The NM_006586.5(CNPY3):​c.71_76delTGCTGC​(p.Leu24_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 0.000508 in 1,560,294 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 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (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 nfe. GnomAd4 allele frequency = 0.000388 (59/151950) while in subpopulation NFE AF = 0.000692 (47/67926). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 27 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.71_76delTGCTGC	p.Leu24_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.71_76delTGCTGC	p.Leu24_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.71_76delTGCTGC	p.Leu24_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.71_76delTGCTGC	p.Leu24_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.71_76delTGCTGC	p.Leu24_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.71_76delTGCTGC	p.Leu24_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000334 AC: 43 AN: 128598 AF XY: 0.000302

Gnomad AFR exome AF: 0.000307

Gnomad AMR exome AF: 0.0000971

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000727

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000520 AC: 733 AN: 1408344 Hom.: 0 AF XY: 0.000491 AC XY: 342 AN XY: 696118

African (AFR) AF: 0.000155 AC: 5 AN: 32320

American (AMR) AF: 0.0000545 AC: 2 AN: 36686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 36982

South Asian (SAS) AF: 0.0000497 AC: 4 AN: 80464

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47648

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

European-Non Finnish (NFE) AF: 0.000649 AC: 704 AN: 1085130

Other (OTH) AF: 0.000291 AC: 17 AN: 58416

GnomAD4 genome AF: 0.000388 AC: 59 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.000364 AC XY: 27 AN XY: 74200

African (AFR) AF: 0.000266 AC: 11 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000692 AC: 47 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000348

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.88
Mutation Taster		=147/53	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;