9-133071462-T-G

Variant names:

• chr9-133071462-T-G
• rs587780308
• NM_001807.6:c.1960T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000372080.8(CEL):​c.1960T>G​(p.Ser654Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S654S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 6)
• Consequence: CEL ENST00000372080.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.132
• 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: 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048852503).
• BP6: Variant 9-133071462-T-G is Benign according to our data. Variant chr9-133071462-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128687.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372080.8. 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.1960T>G	p.Ser654Ala	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.1960T>G	p.Ser654Ala	missense	Exon 11 of 11	ENSP00000361151.6

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 6

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.89
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.13
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.039
Sift	Benign	0.044	D
Sift4G	Pathogenic	0.0	D
Vest4		0.12
MVP		0.29
MPC		0.22
ClinPred		0.14	T
GERP RS		-3.3
gMVP		0.033
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: rs587780308; hg19: chr9-135946849; COSMIC: COSV100672945;