ENST00000375943.6:c.95C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000375943.6(CTRC):c.95C>T(p.Thr32Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,614,106 control chromosomes in the GnomAD database, including 1,205 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T32T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 77 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1128 hom. )

Consequence

CTRC
ENST00000375943.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -6.81

Publications

6 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026253164).

BP6

Variant 1-15442501-C-T is Benign according to our data. Variant chr1-15442501-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3 link	c.285C>T	p.Asp95Asp	synonymous_variant	Exon 4 of 8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2 link	c.285C>T	p.Asp95Asp	synonymous_variant	Exon 4 of 7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CTRC	ENST00000375943.6 link	c.95C>T	p.Thr32Met	missense_variant	Exon 2 of 5	1		ENSP00000365110.2
CTRC	ENST00000375949.5 link	c.285C>T	p.Asp95Asp	synonymous_variant	Exon 4 of 8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000476813.5 link	n.107C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3
CTRC	ENST00000483406.1 link	n.195C>T		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3823

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.0506

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.00980

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0346

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0334

AC:

8401

AN:

251370

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.0383

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.0415

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.0351

Gnomad OTH exome

AF:

0.0336

GnomAD4 exome

AF:

0.0354

AC:

51813

AN:

1461824

Hom.:

1128

Cov.:

AF XY:

0.0358

AC XY:

26050

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00576

AC:

193

AN:

33478

American (AMR)

AF:

0.0359

AC:

1606

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

621

AN:

26134

East Asian (EAS)

AF:

0.0797

AC:

3163

AN:

39692

South Asian (SAS)

AF:

0.0468

AC:

4038

AN:

86252

European-Finnish (FIN)

AF:

0.0140

AC:

747

AN:

53412

Middle Eastern (MID)

AF:

0.0544

AC:

314

AN:

5768

European-Non Finnish (NFE)

AF:

0.0352

AC:

39102

AN:

1111980

Other (OTH)

AF:

0.0336

AC:

2029

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

2954

5908

8861

11815

14769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1474

2948

4422

5896

7370

<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:

0.0251

AC:

3827

AN:

152282

Hom.:

Cov.:

AF XY:

0.0242

AC XY:

1802

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00635

AC:

264

AN:

41548

American (AMR)

AF:

0.0307

AC:

470

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3472

East Asian (EAS)

AF:

0.0509

AC:

263

AN:

5164

South Asian (SAS)

AF:

0.0410

AC:

198

AN:

4830

European-Finnish (FIN)

AF:

0.00980

AC:

104

AN:

10614

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0346

AC:

2355

AN:

68030

Other (OTH)

AF:

0.0265

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

181

362

543

724

905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0331

Hom.:

195

Bravo

AF:

0.0250

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0345

AC:

297

ExAC

AF:

0.0338

AC:

4107

EpiCase

AF:

0.0368

EpiControl

AF:

0.0364

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 25, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

May 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18172691, 23135764) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.37

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.10

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.036

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.95

PhyloP100

-6.8

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.076

Vest4

0.066

ClinPred

0.029

GERP RS

-6.2

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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