NM_006586.5:c.71_76dupTGCTGC

Variant names:

• chr6-42929619-T-TTGCTGC
• rs570105218
• NM_006586.5:c.71_76dupTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS1_Supporting

The NM_006586.5(CNPY3):​c.71_76dupTGCTGC​(p.Leu24_Leu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,560,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420
• 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006586.5
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000327 (46/1408518) while in subpopulation NFE AF = 0.0000341 (37/1085236). AF 95% confidence interval is 0.0000252. There are 0 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.71_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.71_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	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_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.71_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.71_76dupTGCTGC	p.Leu24_Leu25dup	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 46 AN: 1408518 Hom.: 0 Cov.: 31 AF XY: 0.0000373 AC XY: 26 AN XY: 696218

African (AFR) AF: 0.0000309 AC: 1 AN: 32322

American (AMR) AF: 0.0000273 AC: 1 AN: 36692

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

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

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80482

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47672

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

European-Non Finnish (NFE) AF: 0.0000341 AC: 37 AN: 1085236

Other (OTH) AF: 0.0000514 AC: 3 AN: 58420

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74200

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.0000655 AC: 1 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: 0.0000947 AC: 1 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: 0.0000364 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=84/16	polymorphism

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;