1-15438466-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_007272.3(CTRC):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,852 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTRC NM_007272.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.77

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_007272.3 (CTRC) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1784172
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-15438466-T-C is Pathogenic according to our data. Variant chr1-15438466-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1798675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTRC	NM_007272.3	c.2T>C	p.Met1?	start_lost	1/8	ENST00000375949.5
CTRC	XM_011540550.2	c.2T>C	p.Met1?	start_lost	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTRC	ENST00000375949.5	c.2T>C	p.Met1?	start_lost	1/8	1	NM_007272.3	P1
CTRC	ENST00000375943.6	c.2T>C	p.Met1?	start_lost	1/5	1
CTRC	ENST00000476813.5	n.14T>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727216

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the CTRC gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This amino acid position is highly conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.92		Loss of stability (P = 0.0214);Loss of stability (P = 0.0214);
MVP		0.94
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.83
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-15764962;