chr6-42929619-T-TTGC

Variant names:

• chr6-42929619-T-TTGC
• rs570105218
• NM_006586.5:c.74_76dupTGC

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.74_76dupTGC​(p.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 0.000733 in 1,560,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B: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 -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006586.5
• BP6: Variant 6-42929619-T-TTGC is Benign according to our data. Variant chr6-42929619-T-TTGC is described in ClinVar as Likely_benign. ClinVar VariationId is 3047364.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000756 (115/152066) while in subpopulation SAS AF = 0.00207 (10/4826). AF 95% confidence interval is 0.00112. There are 0 homozygotes in GnomAd4. There are 60 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.74_76dupTGC	p.Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.74_76dupTGC	p.Leu25dup	disruptive_inframe_insertion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.74_76dupTGC	p.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.74_76dupTGC	p.Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.74_76dupTGC	p.Leu25dup	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.74_76dupTGC	p.Leu25dup	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00107 AC: 138 AN: 128598 AF XY: 0.00105

Gnomad AFR exome AF: 0.000768

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.000146

Gnomad EAS exome AF: 0.000642

Gnomad FIN exome AF: 0.0000880

Gnomad NFE exome AF: 0.000864

Gnomad OTH exome AF: 0.00190

GnomAD4 exome AF: 0.000731 AC: 1029 AN: 1408478 Hom.: 0 Cov.: 31 AF XY: 0.000766 AC XY: 533 AN XY: 696190

African (AFR) AF: 0.00105 AC: 34 AN: 32322

American (AMR) AF: 0.00158 AC: 58 AN: 36694

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25260

East Asian (EAS) AF: 0.000649 AC: 24 AN: 36980

South Asian (SAS) AF: 0.00160 AC: 129 AN: 80480

European-Finnish (FIN) AF: 0.000210 AC: 10 AN: 47672

Middle Eastern (MID) AF: 0.000917 AC: 5 AN: 5450

European-Non Finnish (NFE) AF: 0.000653 AC: 709 AN: 1085202

Other (OTH) AF: 0.00101 AC: 59 AN: 58418

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.000807 AC XY: 60 AN XY: 74326

African (AFR) AF: 0.000843 AC: 35 AN: 41526

American (AMR) AF: 0.00105 AC: 16 AN: 15286

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

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5168

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10564

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67918

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000219 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CNPY3-related disorder (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; COSMIC: COSV58976272; COSMIC: COSV58976272;