1-15438466-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_007272.3(CTRC):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CTRC
NM_007272.3 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.77

Publications

0 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.

PVS1

Start lost variant, next in-frame start position is after 21 pathogenic variants. Next in-frame start position is after 200 codons. Genomic position: 15444710. Lost 0.741 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-15438466-T-C is Pathogenic according to our data. Variant chr1-15438466-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1798675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENST00000375949.5	NP_009203.2	Q99895
CTRC	XM_011540550.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTRC	ENST00000375949.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	1	NM_007272.3	ENSP00000365116.4	Q99895
CTRC	ENST00000375943.6 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	1		ENSP00000365110.2	Q68DR9
CTRC	ENST00000476813.5 link	n.14T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:1

Feb 10, 2022

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the CTRC gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This amino acid position is highly conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.085

T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.55

PhyloP100

2.8

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.75

MutPred

0.92

Loss of stability (P = 0.0214);Loss of stability (P = 0.0214);

MVP

0.94

ClinPred

0.98

GERP RS

4.2

PromoterAI

-0.054

Neutral

(source)

Varity_R

0.83

gMVP

0.66

Mutation Taster

=35/165

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over