9-133070628-T-C

Variant names:

• chr9-133070628-T-C
• rs77696629
• NM_001807.6:c.1454T>C

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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.40
• Publications: 20 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

ACMG classification

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.

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.1454T>C	p.Ile485Thr	missense	Exon 10 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.1454T>C	p.Ile485Thr	missense	Exon 10 of 11	ENSP00000361151.6	P19835-1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 2741 AN: 105760 Hom.: 10 Cov.: 29

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

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.: 61 Cov.: 32 AF XY: 0.00831 AC XY: 5442 AN XY: 654874

⚠️ 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: 43 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: 67 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.

GnomAD4 genome AF: 0.0259 AC: 2742 AN: 105858 Hom.: 10 Cov.: 29 AF XY: 0.0253 AC XY: 1320 AN XY: 52106

⚠️ 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: 21 AN: 2460

East Asian (EAS) AF: 0.0149 AC: 57 AN: 3830

South Asian (SAS) AF: 0.0275 AC: 89 AN: 3234

European-Finnish (FIN) AF: 0.0104 AC: 84 AN: 8104

Middle Eastern (MID) AF: 0.0632 AC: 11 AN: 174

European-Non Finnish (NFE) AF: 0.0182 AC: 848 AN: 46616

Other (OTH) AF: 0.0329 AC: 47 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.

Alfa AF: 0.0619 Hom.: 6

ExAC AF: 0.0194 AC: 2341

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Maturity-onset diabetes of the young type 8 (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Transitory neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.37	T
PhyloP100		7.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.35
MPC		1.0
ClinPred		0.014	T
GERP RS		4.6
gMVP		0.73
Mutation Taster		=74/26	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: rs77696629; hg19: chr9-135946015; COSMIC: COSV60826354;