chr6-42929619-TTGC-T

Variant names:

• chr6-42929619-TTGC-T
• rs570105218
• NM_006586.5:c.74_76delTGC

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_76delTGC​(p.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 0.00101 in 1,498,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: CNPY3 NM_006586.5 disruptive_inframe_deletion
• Clinical Significance: 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-TTGC-T is Benign according to our data. Variant chr6-42929619-TTGC-T is described in ClinVar as Benign. ClinVar VariationId is 3060774.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000257 (39/152036) while in subpopulation AFR AF = 0.000674 (28/41520). AF 95% confidence interval is 0.000478. There are 0 homozygotes in GnomAd4. There are 16 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_76delTGC	p.Leu25del	disruptive_inframe_deletion	Exon 1 of 6	NP_006577.2
	CNPY3	NM_001318842.1		c.74_76delTGC	p.Leu25del	disruptive_inframe_deletion	Exon 1 of 7	NP_001305771.1
	CNPY3-GNMT	NM_001318857.2		c.74_76delTGC	p.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.74_76delTGC	p.Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000361926.4	Q9BT09-1
	CNPY3	ENST00000893179.1		c.74_76delTGC	p.Leu25del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000563238.1
	CNPY3	ENST00000924680.1		c.74_76delTGC	p.Leu25del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000594739.1

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151920 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00658 AC: 846 AN: 128598 AF XY: 0.00633

Gnomad AFR exome AF: 0.00768

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00509

Gnomad EAS exome AF: 0.00663

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00624

GnomAD4 exome AF: 0.00110 AC: 1476 AN: 1346290 Hom.: 0 AF XY: 0.00115 AC XY: 763 AN XY: 662990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00199 AC: 61 AN: 30706

American (AMR) AF: 0.00275 AC: 93 AN: 33796

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 35 AN: 23420

East Asian (EAS) AF: 0.00140 AC: 48 AN: 34394

South Asian (SAS) AF: 0.00163 AC: 120 AN: 73830

European-Finnish (FIN) AF: 0.00408 AC: 182 AN: 44562

Middle Eastern (MID) AF: 0.00290 AC: 15 AN: 5180

European-Non Finnish (NFE) AF: 0.000809 AC: 846 AN: 1045134

Other (OTH) AF: 0.00138 AC: 76 AN: 55268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000257 AC: 39 AN: 152036 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74314

African (AFR) AF: 0.000674 AC: 28 AN: 41520

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67908

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

Alfa AF: 0.0187 Hom.: 0

Bravo AF: 0.000302

ClinVar

ClinVar submissions

Significance: 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		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: COSV58975170; COSMIC: COSV58975170;