9-133071594-T-G

Variant names:

• chr9-133071594-T-G
• rs587780310
• NM_001807.6:c.2092T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001807.6(CEL):​c.2092T>G​(p.Ser698Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 15)
  • Exomes 𝑓: 0.00014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEL NM_001807.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.348
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07587674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001807.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEL	NM_001807.6	MANE Select	c.2092T>G	p.Ser698Ala	missense	Exon 11 of 11	NP_001798.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEL	ENST00000372080.8	TSL:5 MANE Select	c.2092T>G	p.Ser698Ala	missense	Exon 11 of 11	ENSP00000361151.6

Frequencies

GnomAD3 genomes AF: 0.000724 AC: 62 AN: 85692 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.000332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00107

Gnomad ASJ AF: 0.000907

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000925

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000922

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.0000978 AC: 14 AN: 143100 AF XY: 0.000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000142 AC: 167 AN: 1177344 Hom.: 0 Cov.: 24 AF XY: 0.000123 AC XY: 72 AN XY: 587460

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

African (AFR) AF: 0.0000355 AC: 1 AN: 28200

American (AMR) AF: 0.000114 AC: 4 AN: 34962

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 26 AN: 22324

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32828

South Asian (SAS) AF: 0.0000261 AC: 2 AN: 76754

European-Finnish (FIN) AF: 0.0000920 AC: 3 AN: 32624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3600

European-Non Finnish (NFE) AF: 0.000139 AC: 125 AN: 896602

Other (OTH) AF: 0.000101 AC: 5 AN: 49450

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000723 AC: 62 AN: 85756 Hom.: 0 Cov.: 15 AF XY: 0.000674 AC XY: 28 AN XY: 41542

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

African (AFR) AF: 0.000331 AC: 8 AN: 24204

American (AMR) AF: 0.00106 AC: 9 AN: 8460

Ashkenazi Jewish (ASJ) AF: 0.000907 AC: 2 AN: 2206

East Asian (EAS) AF: 0.00 AC: 0 AN: 3000

South Asian (SAS) AF: 0.00 AC: 0 AN: 2792

European-Finnish (FIN) AF: 0.000925 AC: 4 AN: 4326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.000922 AC: 36 AN: 39030

Other (OTH) AF: 0.00264 AC: 3 AN: 1136

⚠️ 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.

Alfa AF: 0.00236 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity-onset diabetes of the young type 8 Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

not provided Uncertain:1

Jan 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.35
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MVP		0.66
MPC		0.66
ClinPred		0.19	T
GERP RS		-2.1
gMVP		0.037
Mutation Taster		=99/1	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: rs587780310; hg19: chr9-135946981; COSMIC: COSV104658897;