rs121909293

Positions:

• chr1-15445717-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

The NM_007272.3(CTRC):​c.760C>T​(p.Arg254Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,614,198 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R254P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (28 hom.)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association criteria provided, conflicting classifications P:3 U:2 B:2 O:3
• Conservation: PhyloP100: 1.71

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.020052552).
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRC	NM_007272.3	c.760C>T	p.Arg254Trp	missense_variant	7/8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2	c.614C>T	p.Pro205Leu	missense_variant	6/7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRC	ENST00000375949.5	c.760C>T	p.Arg254Trp	missense_variant	7/8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6	c.*214C>T		3_prime_UTR_variant	4/5	1		ENSP00000365110.2
CTRC	ENST00000483406.1	n.524C>T		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152236 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00443 AC: 1113 AN: 251296 Hom.: 11 AF XY: 0.00439 AC XY: 597 AN XY: 135856

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0247

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00367 AC: 5372 AN: 1461846 Hom.: 28 Cov.: 34 AF XY: 0.00367 AC XY: 2666 AN XY: 727230

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00444 AC XY: 331 AN XY: 74500

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00322 Hom.: 2

Bravo AF: 0.00174

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00400 AC: 485

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity; association

Submissions summary: Pathogenic:3 Uncertain:2 Benign:2 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:3 Uncertain:1 Benign:1 Other:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Dec 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	The CTRC c.760C>T; p.Arg254Trp variant (rs121909293) has been reported in multiple individuals with chronic, hereditary, or recurrent acute pancreatitis, both in the homozygous state and in individuals carrying a second pathogenic variant (Beer 2013, Giefer 2017, Masamune 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013). Functional characterization of p.Arg254Trp indicates a moderate reduction in the level of secreted CTRC protein, but no impact on enzymatic activity (Beer 2013, Rosendahl 2008), leading to its designation as a moderate-to-low-risk variant (Beer 2013). The variant is reported in ClinVar (Variation ID: 8178) and is found in the general population with an overall allele frequency of 0.46% (1305/282668 alleles, including 12 homozygotes) in the Genome Aggregation Database. However, it is reported to be at a higher frequency in affected European individuals compared to controls (Beer 2013, Masson 2008, Rosendahl 2008, Rosendahl 2013), and to co-occur at increased frequency with the SPINK1 p.Asn34Ser variant in affected individuals (Rosendahl 2008). The arginine at residue 254 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.809). Based on available information, this variant is considered to be likely pathogenic. 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; 62(11):1616-24. PMID: 22942235 Giefer MJ et al. Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations. J Pediatr. 2017 Jul;186:95-100. PMID: 28502372 LaRusch J et al. The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol. 2015 Jan 8;6:e68. PMID: 25569187 Masamune A et al. Identification of novel missense CTRC variants in Japanese patients with chronic pancreatitis. Gut. 2013; 62(4):653-4. PMID: 23135764 Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008; 123(1):83-91. PMID: 18172691 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 Rosendahl J et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008; 40(1):78-82. PMID: 18059268 -
association, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the CTRC protein (p.Arg254Trp). This variant is present in population databases (rs121909293, gnomAD 2.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with chronic pancreatitis and in unaffected controls. Overall it has been reported to confer ~3-fold increased risk for chronic pancreatitis in heterozygous carriers (PMID: 18059268, 18172691, 22427236, 22942235, 25569187). ClinVar contains an entry for this variant (Variation ID: 8178). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTRC protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTRC function (PMID: 18059268, 19453252). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2022	The p.R254W pathogenic mutation (also known as c.760C>T), located in coding exon 7 of the CTRC gene, results from a C to T substitution at nucleotide position 760. The arginine at codon 254 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been shown to be over-represented in individuals with idiopathic or hereditary chronic pancreatitis; it was demonstrated to cause a reduction in chymotrypsin C activity due to decreased production and/or secretion (Rosendahl J et al. Nat Genet. 2008;40(1):78-82). Another study found this mutation in 2.07% of affected individuals versus 0.57% of control individuals and in vitro studies suggest that this mutation results in slightly decreased protein secretion and increased rate of degradation by trypsin (Beer S et al. Gut. 2013 Nov;62(11):1616-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 18, 2022	Criteria applied: PS3,PM1,PP3,BA1 -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

CTRC: BS1, BS2 -

Pancreatitis, chronic, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.020	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.96
MPC		0.61
ClinPred		0.090	T
GERP RS		4.7
Varity_R		0.91
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909293; hg19: chr1-15772212; COSMIC: COSV65621461; COSMIC: COSV65621461;