NM_001807.6:c.217+35G>A

Variant names:

• chr9-133064589-G-A
• rs8193019
• NM_001807.6:c.217+35G>A

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.217+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,522 control chromosomes in the GnomAD database, including 11 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 0.015 (5 hom., cov: 33)
  • Exomes 𝑓: 0.015 (6 hom.)
• Consequence: CEL NM_001807.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.494
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-133064589-G-A is Benign according to our data. Variant chr9-133064589-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1179684.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.217+35G>A		intron	N/A	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.217+35G>A		intron	N/A	ENSP00000361151.6	P19835-1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2279 AN: 152102 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.0378

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0173 AC: 4295 AN: 248316 AF XY: 0.0190

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0152 AC: 22154 AN: 1461302 Hom.: 6 Cov.: 32 AF XY: 0.0159 AC XY: 11564 AN XY: 726946

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

African (AFR) AF: 0.0162 AC: 542 AN: 33480

American (AMR) AF: 0.00436 AC: 195 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26126

East Asian (EAS) AF: 0.0427 AC: 1694 AN: 39668

South Asian (SAS) AF: 0.0372 AC: 3207 AN: 86228

European-Finnish (FIN) AF: 0.0168 AC: 893 AN: 53270

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5762

European-Non Finnish (NFE) AF: 0.0125 AC: 13892 AN: 1111690

Other (OTH) AF: 0.0155 AC: 935 AN: 60364

⚠️ 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: 0.0150 AC: 2287 AN: 152220 Hom.: 5 Cov.: 33 AF XY: 0.0156 AC XY: 1161 AN XY: 74416

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

African (AFR) AF: 0.0150 AC: 624 AN: 41570

American (AMR) AF: 0.00471 AC: 72 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3462

East Asian (EAS) AF: 0.0411 AC: 212 AN: 5158

South Asian (SAS) AF: 0.0379 AC: 182 AN: 4806

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 863 AN: 67988

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

⚠️ 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: 0.0138 Hom.: 0

Bravo AF: 0.0133

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.6
DANN	Benign	0.37
PhyloP100		0.49
Mutation Taster		=100/0	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: rs8193019; hg19: chr9-135939976; COSMIC: COSV60827375;