9-133070628-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001807.6(CEL):c.1454T>C(p.Ile485Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00906 in 1,436,658 control chromosomes in the GnomAD database, including 71 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 10 hom., cov: 29)

Exomes 𝑓: 0.0077 ( 61 hom. )

Consequence

CEL
NM_001807.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.40

Publications

20 publications found

Variant links:

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

CEL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009507239).

BP6

Variant 9-133070628-T-C is Benign according to our data. Variant chr9-133070628-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 393421.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 link	c.1454T>C	p.Ile485Thr	missense_variant	Exon 10 of 11	ENST00000372080.8	NP_001798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEL	ENST00000372080.8 link	c.1454T>C	p.Ile485Thr	missense_variant	Exon 10 of 11	5	NM_001807.6	ENSP00000361151.6

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

2741

AN:

105760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0454

Gnomad AMI

AF:

0.0105

Gnomad AMR

AF:

0.0249

Gnomad ASJ

AF:

0.00854

Gnomad EAS

AF:

0.0151

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.0684

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.0332

GnomAD2 exomes

AF:

0.00811

AC:

1752

AN:

216088

AF XY:

0.00806

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.00551

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00164

Gnomad FIN exome

AF:

0.00441

Gnomad NFE exome

AF:

0.00914

Gnomad OTH exome

AF:

0.00883

GnomAD4 exome

AF:

0.00772

AC:

10280

AN:

1330800

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

5442

AN XY:

654874

show subpopulations

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

African (AFR)

AF:

0.0208

AC:

620

AN:

29846

American (AMR)

AF:

0.00703

AC:

268

AN:

38108

Ashkenazi Jewish (ASJ)

AF:

0.00489

AC:

106

AN:

21698

East Asian (EAS)

AF:

0.00118

AC:

AN:

36496

South Asian (SAS)

AF:

0.0101

AC:

708

AN:

69814

European-Finnish (FIN)

AF:

0.00485

AC:

226

AN:

46554

Middle Eastern (MID)

AF:

0.0126

AC:

AN:

5302

European-Non Finnish (NFE)

AF:

0.00759

AC:

7809

AN:

1029182

Other (OTH)

AF:

0.00805

AC:

433

AN:

53800

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

410

821

1231

1642

2052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0259

AC:

2742

AN:

105858

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1320

AN XY:

52106

show subpopulations

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

African (AFR)

AF:

0.0454

AC:

1318

AN:

29002

American (AMR)

AF:

0.0250

AC:

261

AN:

10440

Ashkenazi Jewish (ASJ)

AF:

0.00854

AC:

AN:

2460

East Asian (EAS)

AF:

0.0149

AC:

AN:

3830

South Asian (SAS)

AF:

0.0275

AC:

AN:

3234

European-Finnish (FIN)

AF:

0.0104

AC:

AN:

8104

Middle Eastern (MID)

AF:

0.0632

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.0182

AC:

848

AN:

46616

Other (OTH)

AF:

0.0329

AC:

AN:

1428

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.351

Heterozygous variant carriers

245

489

734

978

1223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0619

Hom.:

ExAC

AF:

0.0194

AC:

2341

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 12, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Maturity-onset diabetes of the young type 8

Benign:1

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Feb 08, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BA1 (2.8% in gnomAD Africans and 1% in gnomAD ENF) (BP4/3 predictors + PP3/7 predictors + REVEL 0.615: conflicting evidence, not using both)= Benign -

Transitory neonatal diabetes mellitus

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

CEL gene mutations are associated with MODY and neonatal diabetes. rs77696629 of CEL gene plays a role in increasing the risk of chronic pancreatitis. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.37

PhyloP100

7.4

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Vest4

0.35

MPC

1.0

ClinPred

0.014

GERP RS

4.6

gMVP

0.73

Mutation Taster

=74/26

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over