6-42929619-TTGCTGCTGCTGCTGCTGC-TTGC

Variant names:

• chr6-42929619-TTGCTGCTGCTGCTGC-T
• rs570105218
• NM_006586.5:c.62_76delTGCTGCTGCTGCTGC

Variant summary

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

The NM_006586.5(CNPY3):​c.62_76delTGCTGCTGCTGCTGC​(p.Leu21_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 0.0000237 in 1,560,468 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L21L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• 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. GnomAdExome4 allele frequency = 0.0000256 (36/1408518) while in subpopulation SAS AF = 0.000174 (14/80482). AF 95% confidence interval is 0.000105. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. 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.62_76delTGCTGCTGCTGCTGC	p.Leu21_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.62_76delTGCTGCTGCTGCTGC	p.Leu21_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.62_76delTGCTGCTGCTGCTGC	p.Leu21_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.62_76delTGCTGCTGCTGCTGC	p.Leu21_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.62_76delTGCTGCTGCTGCTGC	p.Leu21_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.62_76delTGCTGCTGCTGCTGC	p.Leu21_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000256 AC: 36 AN: 1408518 Hom.: 0 AF XY: 0.0000273 AC XY: 19 AN XY: 696216

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 36694

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 36984

South Asian (SAS) AF: 0.000174 AC: 14 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: 0.0000194 AC: 21 AN: 1085236

Other (OTH) AF: 0.0000171 AC: 1 AN: 58420

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74200

African (AFR) AF: 0.0000242 AC: 1 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 67926

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=91/109	disease causing (long InDel)

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;