rs769324644
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_007272.3(CTRC):c.139C>T(p.Leu47Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,086 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
CTRC
NM_007272.3 missense
NM_007272.3 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 7.57
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.935
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTRC | NM_007272.3 | c.139C>T | p.Leu47Phe | missense_variant | 3/8 | ENST00000375949.5 | |
CTRC | XM_011540550.2 | c.139C>T | p.Leu47Phe | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTRC | ENST00000375949.5 | c.139C>T | p.Leu47Phe | missense_variant | 3/8 | 1 | NM_007272.3 | P1 | |
CTRC | ENST00000375943.6 | c.41-1948C>T | intron_variant | 1 | |||||
CTRC | ENST00000483406.1 | n.49C>T | non_coding_transcript_exon_variant | 2/6 | 5 | ||||
CTRC | ENST00000476813.5 | n.53-1948C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152236Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251370Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135866
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727228
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152236Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary pancreatitis Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2022 | The p.L47F variant (also known as c.139C>T), located in coding exon 3 of the CTRC gene, results from a C to T substitution at nucleotide position 139. The leucine at codon 47 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 26, 2019 | The CTRC c.139C>T; p.Leu47Phe variant (rs769324644), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 567210). This variant is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 47 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu47Phe variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | 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. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 47 of the CTRC protein (p.Leu47Phe). This variant is present in population databases (rs769324644, gnomAD 0.004%). 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: 567210). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CTRC protein function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K51 (P = 0.0924);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at