1-15438475-T-C

Variant names:

• chr1-15438475-T-C
• rs761548318
• NM_007272.3:c.11T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007272.3(CTRC):​c.11T>C​(p.Ile4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I4I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17394027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3	c.11T>C	p.Ile4Thr	missense_variant	Exon 1 of 8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2	c.11T>C	p.Ile4Thr	missense_variant	Exon 1 of 7		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTRC	ENST00000375949.5	c.11T>C	p.Ile4Thr	missense_variant	Exon 1 of 8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6	c.11T>C	p.Ile4Thr	missense_variant	Exon 1 of 5	1		ENSP00000365110.2
CTRC	ENST00000476813.5	n.23T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4 of the CTRC protein (p.Ile4Thr). This variant is present in population databases (rs761548318, gnomAD 0.0009%). 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: 1747184). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CTRC protein function with a negative predictive value of 95%. 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. -

Dec 30, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I4T variant (also known as c.11T>C), located in coding exon 1 of the CTRC gene, results from a T to C substitution at nucleotide position 11. The isoleucine at codon 4 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.37	T;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.62	N;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N;D
REVEL	Benign	0.22
Sift	Benign	0.53	T;.
Sift4G	Benign	0.17	T;.
Polyphen		0.38	B;.
Vest4		0.29
MutPred		0.57		Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);
MVP		0.85
MPC		0.26
ClinPred		0.17	T
GERP RS		4.0
Varity_R		0.068
gMVP		0.45

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

Other links and lift over

dbSNP: rs761548318; hg19: chr1-15764971;