rs201486613

Positions:

chr1-15445631-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

The NM_007272.3(CTRC):c.674A>C(p.Glu225Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,614,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. E225E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

CTRC
NM_007272.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.522

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 Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016462207).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000259 (378/1461890) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000401. There are 1 homozygotes in gnomad4_exome. There are 201 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRC	NM_007272.3 link	c.674A>C	p.Glu225Ala	missense_variant	7/8	ENST00000375949.5	NP_009203.2	Q99895
CTRC	XM_011540550.2 link	c.528A>C	p.Gly176Gly	synonymous_variant	6/7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CTRC	ENST00000375949.5 link	c.674A>C	p.Glu225Ala	missense_variant	7/8	1	NM_007272.3	ENSP00000365116.4	Q99895
CTRC	ENST00000375943.6 link	c.*128A>C		3_prime_UTR_variant	4/5	1		ENSP00000365110.2	Q68DR9
CTRC	ENST00000483406.1 link	n.438A>C		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000437

AC:

110

AN:

251450

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000259

AC:

378

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

201

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00436

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000217

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000527

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000453

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:3Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 01, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2020	The CTRC c.674A>C; p.Glu225Ala variant (rs201486613) is described in the medical literature in individuals with pancreatitis (Beer 2013, Koziel 2015), but also described in unaffected individuals (Koziel 2015, Rosendahl 2008, Zhou 2011). This variant is reported in ClinVar (Variation ID: 240766). It is found in the general population with an overall allele frequency of 0.04% (115/282830 alleles, including 1 homozygote) in the Genome Aggregation Database. The glutamic acid at codon 225 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, experiments in cell culture show this variant does not affect protein stability or activity (Beer 2013). Considering available information, there is insufficient evidence to classify this variant with certainty. 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. Koziel D et al. Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. BMC Gastroenterol. 2015 Jun 23;15:70. 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. Zhou J et al. Chymotrypsin C mutations in chronic pancreatitis. J Gastroenterol Hepatol. 2011 Aug;26(8):1238-46. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2023	The p.E225A variant (also known as c.674A>C), located in coding exon 7 of the CTRC gene, results from an A to C substitution at nucleotide position 674. The glutamic acid at codon 225 is replaced by alanine, an amino acid with dissimilar properties. This variant has been identified in individuals with pancreatitis and healthy controls (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Koziel D et al. BMC Gastroenterol, 2015 Jun;15:70; Sofia VM et al. Mol. Med., 2016 Sep;22:300-309; Beer S et al. Gut, 2013 Nov;62:1616-24; Cordero-Vázquez E et al. Endocrinol Diabetes Nutr (Engl Ed), 2022 Feb;69:155-156). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.078

DEOGEN2

Benign

0.13

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.83

M_CAP

Benign

0.046

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.52

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.050

REVEL

Benign

0.19

Sift

Benign

0.86

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.26

MVP

0.81

MPC

0.20

ClinPred

0.017

GERP RS

3.4

Varity_R

0.12

gMVP

0.67

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

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