rs193922638

Variant names:

• chr9-133071270-GC-G
• rs193922638
• NM_001807.6:c.1776delC

Your query was ambiguous. Multiple possible variants found:

• chr9-133071270-GC-G
• chr9-133071270-GC-GCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001807.6(CEL):​c.1776delC​(p.Val593CysfsTer111) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P592P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEL NM_001807.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.457
• Publications: 8 publications found

Genes affected

CEL (HGNC:1848): (carboxyl ester lipase) The protein encoded by this gene is a glycoprotein secreted from the pancreas into the digestive tract and from the lactating mammary gland into human milk. The physiological role of this protein is in cholesterol and lipid-soluble vitamin ester hydrolysis and absorption. This encoded protein promotes large chylomicron production in the intestine. Also its presence in plasma suggests its interactions with cholesterol and oxidized lipoproteins to modulate the progression of atherosclerosis. In pancreatic tumoral cells, this encoded protein is thought to be sequestrated within the Golgi compartment and is probably not secreted. This gene contains a variable number of tandem repeat (VNTR) polymorphism in the coding region that may influence the function of the encoded protein. [provided by RefSeq, Jul 2008]

CEL Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 8

  Inheritance: AD, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.215 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 9-133071270-GC-G is Pathogenic according to our data. Variant chr9-133071270-GC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 35815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEL	NM_001807.6	c.1776delC	p.Val593CysfsTer111	frameshift_variant	Exon 11 of 11	ENST00000372080.8	NP_001798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEL	ENST00000372080.8	c.1776delC	p.Val593CysfsTer111	frameshift_variant	Exon 11 of 11	5	NM_001807.6	ENSP00000361151.6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 128584 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.0000144 AC: 2 AN: 139284 AF XY: 0.0000130

Gnomad AFR exome AF: 0.000151

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000155

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000882 AC: 12 AN: 1361032 Hom.: 0 Cov.: 32 AF XY: 0.00000890 AC XY: 6 AN XY: 674202

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

African (AFR) AF: 0.00 AC: 0 AN: 30980

American (AMR) AF: 0.00 AC: 0 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24800

East Asian (EAS) AF: 0.00 AC: 0 AN: 35808

South Asian (SAS) AF: 0.000114 AC: 9 AN: 79030

European-Finnish (FIN) AF: 0.0000285 AC: 1 AN: 35056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056034

Other (OTH) AF: 0.0000176 AC: 1 AN: 56952

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00240315), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 128584 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 62380

African (AFR) AF: 0.00 AC: 0 AN: 34116

American (AMR) AF: 0.00 AC: 0 AN: 13104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3096

East Asian (EAS) AF: 0.00 AC: 0 AN: 4226

South Asian (SAS) AF: 0.00 AC: 0 AN: 3646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59270

Other (OTH) AF: 0.00 AC: 0 AN: 1710

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 8 Pathogenic:3

Jan 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Val596Cysfs variant in CEL has been reported in 4 individuals with Maturity-Onset Diabetes of the Young, segregated with disease in four affected relatives from one family (PMID: 16369531). This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 35815). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 596 and leads to a premature termination codon 111 amino acids downstream. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the CEL gene is an established disease mechanism in MODY type 8. The p.Val596Cysfs is located in a region of CEL that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 16369531). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1, PM1, PVS1_moderate (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
Mutation Taster		=37/163	disease causing (ClinVar)

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: rs193922638; hg19: chr9-135946657; COSMIC: COSV60826310;