rs760962602

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_007272.3(CTRC):​c.719G>A​(p.Arg240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CTRC
NM_007272.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.183
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_007272.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.066589296).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTRCNM_007272.3 linkc.719G>A p.Arg240Gln missense_variant Exon 7 of 8 ENST00000375949.5 NP_009203.2 Q99895
CTRCXM_011540550.2 linkc.573G>A p.Pro191Pro synonymous_variant Exon 6 of 7 XP_011538852.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTRCENST00000375949.5 linkc.719G>A p.Arg240Gln missense_variant Exon 7 of 8 1 NM_007272.3 ENSP00000365116.4 Q99895
CTRCENST00000375943.6 linkc.*173G>A 3_prime_UTR_variant Exon 4 of 5 1 ENSP00000365110.2 Q68DR9
CTRCENST00000483406.1 linkn.483G>A non_coding_transcript_exon_variant Exon 5 of 6 5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152148
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251258
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461870
Hom.:
0
Cov.:
34
AF XY:
0.0000179
AC XY:
13
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152148
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary pancreatitis Uncertain:4
Mar 17, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 07, 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.719G>A; p.Arg240Gln variant (rs760962602), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 581364). This variant is found in the general population with an overall allele frequency of 0.003% (8/251,258 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.194). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Feb 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R240Q variant (also known as c.719G>A), located in coding exon 7 of the CTRC gene, results from a G to A substitution at nucleotide position 719. The arginine at codon 240 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in individuals with chronic pancreatitis (Brownell JN et al. Pancreas, 2020 Sep;49:e76-e78; Cheema HA et al. Turk J Gastroenterol, 2023 Oct;34:1088-1098). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 240 of the CTRC protein (p.Arg240Gln). This variant is present in population databases (rs760962602, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CTRC-related conditions. ClinVar contains an entry for this variant (Variation ID: 581364). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CTRC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
May 10, 2022
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
11
DANN
Benign
0.91
DEOGEN2
Benign
0.15
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.067
T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
-0.19
N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.41
N
REVEL
Benign
0.19
Sift
Benign
0.062
T
Sift4G
Benign
0.24
T
Polyphen
0.063
B
Vest4
0.24
MutPred
0.32
Loss of MoRF binding (P = 0.02);
MVP
0.52
MPC
0.21
ClinPred
0.045
T
GERP RS
1.6
Varity_R
0.10
gMVP
0.50

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.

Other links and lift over

dbSNP: rs760962602; hg19: chr1-15772171; API