rs121909293

Variant names:

• chr1-15445717-C-T
• rs121909293
• NM_007272.3:c.760C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 5P and 12B. PS3 PP3 BP4_Strong BS1 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). ClinVar reports functional evidence for this variant: "SCV000603259: 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). PMID:22942235" and additional evidence is available in ClinVar. 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:4 U:3 B:1 O:3
• Conservation: PhyloP100: 1.71
• Publications: 55 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000603259: 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). PMID: 22942235; SCV001189039: This variant 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 variant in 2.07% of affected individuals versus 0.57% of control individuals and in vitro studies suggest that this variant results in slightly decreased protein secretion and increased rate of degradation by trypsin (Beer S et al. Gut. 2013 Nov;62(11):1616-24).
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.020052552).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00371 (565/152352) while in subpopulation NFE AF = 0.0041 (279/68034). AF 95% confidence interval is 0.0037. There are 5 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 565 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007272.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRC	NM_007272.3	MANE Select	c.760C>T	p.Arg254Trp	missense	Exon 7 of 8	NP_009203.2	Q99895

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRC	ENST00000375949.5	TSL:1 MANE Select	c.760C>T	p.Arg254Trp	missense	Exon 7 of 8	ENSP00000365116.4	Q99895
	CTRC	ENST00000375943.6	TSL:1	c.*214C>T		3_prime_UTR	Exon 4 of 5	ENSP00000365110.2	Q68DR9
	CTRC	ENST00000483406.1	TSL:5	n.524C>T		non_coding_transcript_exon	Exon 5 of 6

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

GnomAD2 exomes AF: 0.00443 AC: 1113 AN: 251296 AF XY: 0.00439

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 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

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00143 AC: 123 AN: 86258

European-Finnish (FIN) AF: 0.0233 AC: 1245 AN: 53380

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00345 AC: 3834 AN: 1112004

Other (OTH) AF: 0.00227 AC: 137 AN: 60396

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

African (AFR) AF: 0.000409 AC: 17 AN: 41586

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0235 AC: 250 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00319 Hom.: 5

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; association

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Hereditary pancreatitis (7)
-	-	1	not provided (1)
-	1	-	not specified (1)
1	-	-	Pancreatitis, chronic, susceptibility to (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.7
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
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

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