1-15438477-A-T

Variant summary

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

The NM_007272.3(CTRC):c.13A>T(p.Thr5Ser) 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. 14/21 in silico tools predict 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. T5P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.317

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=0.11577341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTRC	NM_007272.3	c.13A>T	p.Thr5Ser	missense_variant	1/8	ENST00000375949.5
CTRC	XM_011540550.2	c.13A>T	p.Thr5Ser	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTRC	ENST00000375949.5	c.13A>T	p.Thr5Ser	missense_variant	1/8	1	NM_007272.3	P1
CTRC	ENST00000375943.6	c.13A>T	p.Thr5Ser	missense_variant	1/5	1
CTRC	ENST00000476813.5	n.25A>T		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 12, 2021	The p.T5S variant (also known as c.13A>T), located in coding exon 1 of the CTRC gene, results from an A to T substitution at nucleotide position 13. The threonine at codon 5 is replaced by serine, an amino acid with 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 06, 2023	The CTRC c.13A>T; p.Thr5Ser variant (rs933703), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1771755). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is neutral (REVEL: 0.12). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	12
Dann	Benign	0.79
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.39	T;.
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.16	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;D
REVEL	Benign	0.12
Sift	Benign	0.072	T;.
Sift4G	Benign	0.11	T;.
Polyphen		0.13	B;.
Vest4		0.087
MutPred		0.49		Gain of disorder (P = 0.037);Gain of disorder (P = 0.037);
MVP		0.84
MPC		0.17
ClinPred		0.15	T
GERP RS		1.0
Varity_R		0.048
gMVP		0.40

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: rs933703; hg19: chr1-15764973;