1-15438477-A-C

Variant names:

• chr1-15438477-A-C
• rs933703
• NM_007272.3:c.13A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007272.3(CTRC):​c.13A>C​(p.Thr5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27423435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRC	NM_007272.3	c.13A>C	p.Thr5Pro	missense_variant	Exon 1 of 8	ENST00000375949.5	NP_009203.2
CTRC	XM_011540550.2	c.13A>C	p.Thr5Pro	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.13A>C	p.Thr5Pro	missense_variant	Exon 1 of 8	1	NM_007272.3	ENSP00000365116.4
CTRC	ENST00000375943.6	c.13A>C	p.Thr5Pro	missense_variant	Exon 1 of 5	1		ENSP00000365110.2
CTRC	ENST00000476813.5	n.25A>C		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T5P variant (also known as c.13A>C), located in coding exon 1 of the CTRC gene, results from an A to C substitution at nucleotide position 13. The threonine at codon 5 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. 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	0.14
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.50	T;.
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.65	N;.
PhyloP100		0.32
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.018	D;.
Polyphen		0.83	P;.
Vest4		0.33
MutPred		0.59		Loss of glycosylation at T5 (P = 0.0601);Loss of glycosylation at T5 (P = 0.0601);
MVP		0.90
MPC		0.24
ClinPred		0.23	T
GERP RS		1.0
PromoterAI		-0.021	Neutral
Varity_R		0.32
gMVP		0.50
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs933703; hg19: chr1-15764973;