chr9-133062009-C-T

Variant names:

• chr9-133062009-C-T
• rs201383133
• NM_001807.6:c.7C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001807.6(CEL):​c.7C>T​(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,549,678 control chromosomes in the GnomAD database, including 20 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 0.0061 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0016 (16 hom.)
• Consequence: CEL NM_001807.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.86
• Publications: 3 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: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296375 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061931014).
• BP6: Variant 9-133062009-C-T is Benign according to our data. Variant chr9-133062009-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEL	NM_001807.6	MANE Select	c.7C>T	p.Arg3Cys	missense	Exon 1 of 11	NP_001798.3	P19835-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEL	ENST00000372080.8	TSL:5 MANE Select	c.7C>T	p.Arg3Cys	missense	Exon 1 of 11	ENSP00000361151.6	P19835-1
	ENSG00000296375	ENST00000738634.1		n.*210C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 913 AN: 151808 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00243 AC: 375 AN: 154382 AF XY: 0.00186

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00485

GnomAD4 exome AF: 0.00160 AC: 2241 AN: 1397752 Hom.: 16 Cov.: 32 AF XY: 0.00146 AC XY: 1008 AN XY: 689112

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

African (AFR) AF: 0.0234 AC: 736 AN: 31478

American (AMR) AF: 0.00359 AC: 129 AN: 35932

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 49 AN: 25152

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35692

South Asian (SAS) AF: 0.000227 AC: 18 AN: 79182

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 48938

Middle Eastern (MID) AF: 0.0108 AC: 60 AN: 5552

European-Non Finnish (NFE) AF: 0.000966 AC: 1041 AN: 1077990

Other (OTH) AF: 0.00356 AC: 206 AN: 57836

⚠️ 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 AF: 0.00609 AC: 925 AN: 151926 Hom.: 4 Cov.: 30 AF XY: 0.00572 AC XY: 425 AN XY: 74280

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

African (AFR) AF: 0.0188 AC: 777 AN: 41268

American (AMR) AF: 0.00452 AC: 69 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67984

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

⚠️ 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: 0.00151 Hom.: 0

ESP6500AA AF: 0.0123 AC: 43

ESP6500EA AF: 0.00103 AC: 8

ExAC AF: 0.00108 AC: 97

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.57	T
PhyloP100		2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.33
MVP		0.84
MPC		1.2
ClinPred		0.017	T
GERP RS		4.8
PromoterAI		-0.0098	Neutral
gMVP		0.67
Mutation Taster		=98/2	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: rs201383133; hg19: chr9-135937396; COSMIC: COSV99053334; COSMIC: COSV99053334;