NM_006586.5:c.65_76delTGCTGCTGCTGC

Variant names:

• chr6-42929619-TTGCTGCTGCTGC-T
• rs570105218
• NM_006586.5:c.65_76delTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS1

The NM_006586.5(CNPY3):​c.65_76delTGCTGCTGCTGC​(p.Leu22_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 0.000226 in 1,560,586 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006586.5
• BP6: Variant 6-42929619-TTGCTGCTGCTGC-T is Benign according to our data. Variant chr6-42929619-TTGCTGCTGCTGC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2582320.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000401 (61/152066) while in subpopulation EAS AF = 0.00948 (49/5168). AF 95% confidence interval is 0.00737. There are 0 homozygotes in GnomAd4. There are 35 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.65_76delTGCTGCTGCTGC	p.Leu22_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.65_76delTGCTGCTGCTGC	p.Leu22_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.65_76delTGCTGCTGCTGC	p.Leu22_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.65_76delTGCTGCTGCTGC	p.Leu22_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.65_76delTGCTGCTGCTGC	p.Leu22_Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.65_76delTGCTGCTGCTGC	p.Leu22_Leu25del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00946

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000947

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000591 AC: 76 AN: 128598 AF XY: 0.000632

Gnomad AFR exome AF: 0.000307

Gnomad AMR exome AF: 0.000340

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00663

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000785

Gnomad OTH exome AF: 0.000271

GnomAD4 exome AF: 0.000207 AC: 291 AN: 1408520 Hom.: 0 AF XY: 0.000204 AC XY: 142 AN XY: 696218

African (AFR) AF: 0.0000619 AC: 2 AN: 32322

American (AMR) AF: 0.000218 AC: 8 AN: 36694

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

East Asian (EAS) AF: 0.00522 AC: 193 AN: 36984

South Asian (SAS) AF: 0.000149 AC: 12 AN: 80482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47672

Middle Eastern (MID) AF: 0.000367 AC: 2 AN: 5450

European-Non Finnish (NFE) AF: 0.0000544 AC: 59 AN: 1085236

Other (OTH) AF: 0.000257 AC: 15 AN: 58420

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74326

African (AFR) AF: 0.000169 AC: 7 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00948 AC: 49 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000947 AC: 1 AN: 10564

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67918

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

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000484

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 60 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=127/73	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; COSMIC: COSV100485878; COSMIC: COSV100485878;