rs201012268

chr9-133071121-G-Achr9-133071121-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001807.6(CEL):c.1619G>A(p.Arg540His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000897 in 1,609,546 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 31)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: CEL NM_001807.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.287

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007852435).
• BP6: Variant 9-133071121-G-A is Benign according to our data. Variant chr9-133071121-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 393422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133071121-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0046 (699/151988) while in subpopulation AFR AF= 0.0158 (656/41450). AF 95% confidence interval is 0.0148. There are 7 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 693 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEL	NM_001807.6	c.1619G>A	p.Arg540His	missense_variant	11/11	ENST00000372080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEL	ENST00000372080.8	c.1619G>A	p.Arg540His	missense_variant	11/11	5	NM_001807.6	P1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 693 AN: 151872 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.0000442

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00116 AC: 280 AN: 241210 Hom.: 2 AF XY: 0.000894 AC XY: 118 AN XY: 131932

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000602

Gnomad NFE exome AF: 0.0000720

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000510 AC: 744 AN: 1457558 Hom.: 7 Cov.: 34 AF XY: 0.000451 AC XY: 327 AN XY: 725300

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00460 AC: 699 AN: 151988 Hom.: 7 Cov.: 31 AF XY: 0.00472 AC XY: 351 AN XY: 74300

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.00559

ESP6500AA AF: 0.0171 AC: 66

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00146 AC: 176

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 21, 2018

ACMG criteria: BA1 (1.6% MAF in gnomAD Africans)=benign (REVEL 0.161 + BP4/9 predictors= conflicting evidence, not using) -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.7
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.16
Sift	Benign	0.047	D
Sift4G	Benign	0.18	T
Vest4		0.062
MVP		0.64
MPC		0.30
ClinPred		0.022	T
GERP RS		-5.3
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs201012268; hg19: chr9-135946508;