rs140993290

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_007272.3(CTRC):c.703G>A(p.Val235Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000659 in 1,614,188 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. V235V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00068 ( 6 hom. )

Consequence

CTRC
NM_007272.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 3.66

Publications

33 publications found

Variant links:

Genes affected

CTRC (HGNC:2523): (chymotrypsin C) This gene encodes a member of the peptidase S1 family. The encoded protein is a serum calcium-decreasing factor that has chymotrypsin-like protease activity. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

CTRC Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CTRC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025823325).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000492 (75/152304) while in subpopulation SAS AF = 0.0083 (40/4822). AF 95% confidence interval is 0.00626. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3 link	c.703G>A	p.Val235Ile	missense_variant	Exon 7 of 8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2 link	c.557G>A	p.Arg186His	missense_variant	Exon 6 of 7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CTRC	ENST00000375949.5 link	c.703G>A	p.Val235Ile	missense_variant	Exon 7 of 8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6 link	c.*157G>A		3_prime_UTR_variant	Exon 4 of 5	1		ENSP00000365110.2
CTRC	ENST00000483406.1 link	n.467G>A		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00114

AC:

287

AN:

251446

AF XY:

0.00161

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000676

AC:

988

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000939

AC XY:

683

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00787

AC:

679

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000193

AC:

215

AN:

1112008

Other (OTH)

AF:

0.000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000492

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000375

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00115

AC:

140

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:1Uncertain:2Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V235I pathogenic mutation (also known as c.703G>A), located in coding exon 7 of the CTRC gene, results from a G to A substitution at nucleotide position 703. The valine at codon 235 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with pancreatitis, some of which had additional pathogenic variants in pancreatitis-associated genes (Koziel D et al. BMC Gastroenterol, 2015 Jun;15:70; Werlin S et al. J Pediatr Gastroenterol Nutr, 2015 May;60:675-9; Gaitch N et al. Pancreatology 2016 Apr;16:515-22; Sofia VM et al. Mol Med, 2018 07;24:38). Multiple studies have examined association between this variant and pancreatitis (Masson E et al. Hum Genet, 2008 Feb;123:83-91; Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Derikx MH et al. Eur J Gastroenterol Hepatol, 2009 Aug;21:889-94; Paliwal S et al. Gut, 2013 Nov;62:1602-6; Beer S et al. Gut, 2013 Nov;62:1616-24; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204; Nabi Z et al. Dig Dis Sci, 2020 10;65:3000-3005). In one study, p.V235I was significantly associated with pancreatitis (Paliwal S et al. Gut, 2013 Nov;62:1602-6). Furthermore, in vitro studies showed that this variant does not result in complete loss of function, but slightly reduces CTRC secretion and activity (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Beer S et al. Gut, 2013 Nov;62:1616-24). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CTRC c.703G>A; p.Val235Ile variant (rs140993290) is reported in the medical literature in several individuals with chronic pancreatitis, with several carrying additional pathogenic variants (Hirai 2023, Koziel 2015, Masson 2008, Paliwal 2013, Rosendahl 2008, Rosenhdahl 2014, Tomaiuolo 2015, Wang 2013, Werlin 2015, Zou 2018). This variant is reported in the ClinVar database (Variation ID: 292914), and is found in the general population with an overall allele frequency of 0.10% (293/282822 alleles, including 3 homozygotes) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.797). Additionally, this variant is reported to cause reduced protein activity (Beer 2013, Rosendahl 2008). Although there are indications this variant may be pathogenic, the evidence is conflicting, so the variant is classified as uncertain significance. REFERENCES Beer S et al. Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk. Gut. 2013 Nov;62(11):1616-24. PMID: 22942235. Hirai S et al. The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis. J Pediatr Gastroenterol Nutr. 2023 Apr 1;76(4):483-488. PMID: 36599151. Koziel D et al. Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. BMC Gastroenterol. 2015 Jun 23;15:70. PMID: 26100556. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. PMID: 18172691. Paliwal S et al. Comprehensive screening of chymotrypsin C (CTRC) gene in tropical calcific pancreatitis identifies novel variants. Gut. 2013 Nov;62(11):1602-6. PMID: 22580415. Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008 Jan;40(1):78-82. PMID: 22427236. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. PMID: 22427236. Tomaiuolo AC et al. Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis. J Mol Diagn. 2015 Mar;17(2):171-8. PMID: 25636364. Wang W et al. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. 2013 Sep 3;3(9):e003150. PMID: 24002981. Werlin S et al. Genetic and electrophysiological characteristics of recurrent acute pancreatitis. J Pediatr Gastroenterol Nutr. 2015 May;60(5):675-9. PMID: 25383785. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730. -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.703G>A (p.Val235Ile) variant in CTRC gene has been reported previously as a risk factor in individuals affected with Pancreatitis (Koziel et al. 2015; Nabi et al. 2020; Girodon et al. 2020). Experimental studies show that this variant showed CTRC secretion close to the wild-type levels (~86% of wild type), is resistant to trypsin degradation, and confers a moderate-to-low risk towards pancreatitis (Beer et al. 2013). The p.Val235Ile variant is reported with an allele frequency of 0.11% (287/251446 alleles, including 3 homozygotes) in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Benign / Pathogenic / Uncertain Significance. The reference amino acid at this position in CTRC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 235 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.026

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.1

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.93

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.52

MVP

0.82

MPC

0.63

ClinPred

0.018

GERP RS

4.4

Varity_R

0.67

gMVP

0.57

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over