rs200678111

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007272.3(CTRC):c.533A>G(p.Gln178Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,614,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q178E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

CTRC
NM_007272.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016386509).

BS2

High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTRC	NM_007272.3 linkuse as main transcript	c.533A>G	p.Gln178Arg	missense_variant	6/8	ENST00000375949.5
CTRC	XM_011540550.2 linkuse as main transcript	c.494-952A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CTRC	ENST00000375949.5 linkuse as main transcript	c.533A>G	p.Gln178Arg	missense_variant	6/8	1	NM_007272.3	P1
CTRC	ENST00000375943.6 linkuse as main transcript	c.*94-952A>G		intron_variant		1
CTRC	ENST00000483406.1 linkuse as main transcript	n.404-952A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000784

AC:

197

AN:

251418

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00555

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000148

AC:

216

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000280

ExAC

AF:

0.000766

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	The CTRC c.533A>G; p.Gln178Arg variant (rs200678111) is reported in patients with chronic pancreatitis (Beer 2013, Giefer 2017). However, it has also been found with two mild CFTR pathogenic variants in a pancreatitis patient tested at ARUP Laboratories, and is classified as benign and uncertain in the ClinVar database (Variation ID: 240765). Functional characterizations indicate that the p.Gln178Arg variant has reduced catalytic activity (Beer 2013). The variant is found in the general population with an overall allele frequency of 0.07% (202/282802 alleles, including two homozygotes) in the Genome Aggregation Database, with an increased frequency of 0.55% in Latinos. The glutamine at codon 178 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.423). Due to the conflicting information regarding this variant, its clinical significance is uncertain at this time. 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2023	The p.Q178R variant (also known as c.533A>G), located in coding exon 6 of the CTRC gene, results from an A to G substitution at nucleotide position 533. The glutamine at codon 178 is replaced by arginine, an amino acid with highly similar properties. This variant has been identified in multiple individuals with acute recurrent or chronic pancreatitis (Beer S et al. Gut, 2013 Nov;62:1616-24; Giefer MJ et al. J. Pediatr., 2017 Jul;186:95-100); in vitro studies showed that the catalytic efficiency of this variant was significantly reduced from wild type (Beer S et al. Gut, 2013 Nov;62:1616-24). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CTRC-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2023

The CTRC c.533A>G variant is predicted to result in the amino acid substitution p.Gln178Arg. This variant has been reported in multiple individuals with acute recurrent or chronic pancreatitis and functional studies suggested that this variant results in reduced enzyme activity (Beer et al. 2012. PubMed ID: 22942235; Giefer et al. 2017. PubMed ID: 28502372). However, this variant is also reported in 0.55% of alleles in individuals of Latino descent in gnomAD, including two homozygotes (http://gnomad.broadinstitute.org/variant/1-15771140-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2018

This variant is denoted CTRC c.533A>G at the cDNA level, p.Gln178Arg (Q178R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has been observed in multiple individuals with acute recurrent or chronic pancreatitis (Beer 2013, Giefer 2017). Functional studies have demonstrated that CTRC Gln178Arg is associated with a significant reduction in CTRC catalytic activity (Beer 2013). CTRC Gln178Arg was observed at an allele frequency of 0.57% (192/34420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located within the Peptidase S1 domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CTRC Gln178Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.018

MutationAssessor

Benign

0.84

MutationTaster

Benign

0.62

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.27

Vest4

0.52

MVP

0.87

MPC

0.21

ClinPred

0.16

GERP RS

1.1

Varity_R

0.76

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over