rs515726210

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM4PP3PP5_Very_StrongBS2_Supporting

The NM_007272.3(CTRC):c.738_761delCAAGAAGCCGGTAGTCTACACCCG(p.Lys247_Arg254del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R246R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

CTRC
NM_007272.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: 9.32

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CTRC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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, 19 uncertain in NM_007272.3

PM4

Nonframeshift variant in NON repetitive region in NM_007272.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 1-15445687-AACACCCGCAAGAAGCCGGTAGTCT-A is Pathogenic according to our data. Variant chr1-15445687-AACACCCGCAAGAAGCCGGTAGTCT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 132150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3 link	c.738_761delCAAGAAGCCGGTAGTCTACACCCG	p.Lys247_Arg254del	disruptive_inframe_deletion	Exon 7 of 8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2 link	c.592_615delCAAGAAGCCGGTAGTCTACACCCG	p.Gln198_Pro205del	conservative_inframe_deletion	Exon 6 of 7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CTRC	ENST00000375949.5 link	c.738_761delCAAGAAGCCGGTAGTCTACACCCG	p.Lys247_Arg254del	disruptive_inframe_deletion	Exon 7 of 8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6 link	c.192_215delCAAGAAGCCGGTAGTCTACACCCG		3_prime_UTR_variant	Exon 4 of 5	1		ENSP00000365110.2
CTRC	ENST00000483406.1 link	n.502_525delCAAGAAGCCGGTAGTCTACACCCG		non_coding_transcript_exon_variant	Exon 5 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251286

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000752

AC:

110

AN:

1461868

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

727234

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000881

AC:

AN:

1112006

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000316

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:3Other:1

Jan 31, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.738_761del24 pathogenic mutation (also known as p.K247_R254del) is located in coding exon 7 of the CTRC gene. This mutation results from an in-frame deletion of 24 nucleotides between positions 738 and 761. This results in the deletion of 8 amino acids between codons 247 and 254. In one study, this mutation was significantly overrepresented in the pancreatitis group compared to controls (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82). In another study of individuals of European origin, this mutation was detected in 15/1739 (0.86%) affected individuals and 5/3586 (0.14%) controls (Beer S et al. Gut, 2013 Nov;62:1616-24). In vitro functional studies showed that protein with this variant is catalytically inactive, poorly secreted, and readily degraded by low concentrations of trypsin; the loss of function is hypothesized to increase the risk for chronic pancreatitis (Rosendahl J et al. Nat. Genet., 2008 Jan;40:78-82; Beer S et al. Gut, 2013 Nov;62:1616-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.738_761del, results in the deletion of 8 amino acid(s) of the CTRC protein (p.Lys247_Arg254del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746224507, gnomAD 0.01%). This variant has been observed in individual(s) with CTRC-associated pancreatitis, especially in the European population. In a compiled analysis of four case-control studies involving 1,739 cases and 3,686 controls, this variant was significantly associated with increased risk for pancreatitis (PMID: 18059268, 18172691, 20625975, 22427236, 22942235). ClinVar contains an entry for this variant (Variation ID: 132150). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CTRC function (PMID: 18059268, 22942235). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Nov 18, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Pathogenic:1

Nov 20, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pancreatitis, chronic, susceptibility to

Other:1

Feb 01, 2008

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.3

Mutation Taster

=12/188

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over