1-15438465-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The NM_007272.3(CTRC):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000434 in 1,614,010 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

CTRC
NM_007272.3 start_lost

Scores

6
8
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.93
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 Pathogenic. Variant got 13 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 18 pathogenic variants. Next in-frame start position is after 597 CDS bases. Genomic position: 15444709. Lost 0.740 part of the original CDS.
PS1
Another start lost variant in NM_007272.3 (CTRC) was described as [Likely_pathogenic] in ClinVar as 1798675
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-15438465-A-G is Pathogenic according to our data. Variant chr1-15438465-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1784172.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTRCNM_007272.3 linkc.1A>G p.Met1? start_lost Exon 1 of 8 ENST00000375949.5 NP_009203.2 Q99895
CTRCXM_011540550.2 linkc.1A>G p.Met1? start_lost Exon 1 of 7 XP_011538852.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CTRCENST00000375949.5 linkc.1A>G p.Met1? start_lost Exon 1 of 8 1 NM_007272.3 ENSP00000365116.4 Q99895
CTRCENST00000375943.6 linkc.1A>G p.Met1? start_lost Exon 1 of 5 1 ENSP00000365110.2 Q68DR9
CTRCENST00000476813.5 linkn.13A>G non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152034
Hom.:
0
Cov.:
32
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251464
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461858
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1Uncertain:1
Nov 24, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the CTRC mRNA. The next in-frame methionine is located at codon 200. This variant is present in population databases (rs544668774, 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: 1784172). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Apr 30, 2018
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the CTRC gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.34
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.054
T;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;.
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.71
D
PROVEAN
Uncertain
-2.4
N;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0040
D;.
Polyphen
0.99
D;.
Vest4
0.86
MutPred
0.90
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
0.91
ClinPred
0.93
D
GERP RS
5.3
Varity_R
0.72
gMVP
0.60

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: rs544668774; hg19: chr1-15764961; API