rs201336247

Positions:

• chr9-133065057-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001807.6(CEL):​c.358G>A​(p.Val120Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,613,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: CEL NM_001807.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.47

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11028543).
• BP6: Variant 9-133065057-G-A is Benign according to our data. Variant chr9-133065057-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549532.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEL	NM_001807.6	c.358G>A	p.Val120Ile	missense_variant	4/11	ENST00000372080.8	NP_001798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEL	ENST00000372080.8	c.358G>A	p.Val120Ile	missense_variant	4/11	5	NM_001807.6	ENSP00000361151	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000273 AC: 68 AN: 248840 Hom.: 1 AF XY: 0.000200 AC XY: 27 AN XY: 135144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461196 Hom.: 1 Cov.: 32 AF XY: 0.000216 AC XY: 157 AN XY: 726900

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74448

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000209 Hom.: 2

Bravo AF: 0.000215

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000257 AC: 31

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity-onset diabetes of the young type 8 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 18, 2021	- -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 01, 2017

ACMG Criteria:PP3 (8 predictors), BP4 (2 predictors), BS2 (11 cases and 13 controls in type2diabetesgenetics.org), BP5 (found in case with GCK pathogenic variant) -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.021	D
Vest4		0.40
MVP		0.83
MPC		0.99
ClinPred		0.11	T
GERP RS		2.3
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201336247; hg19: chr9-135940444; COSMIC: COSV60826363;