Variant 1-15438406-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The variant allele was found at a frequency of 0.00215 in 1,604,676 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

intergenic_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -0.0920

Variant links:

Genes affected

(HGNC:):

links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-15438406-C-T is Benign according to our data. Variant chr1-15438406-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240761.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
	use as main transcript	n.15438406C>T	intergenic_region
CTRC	NM_007272.3 linkuse as main transcript	c.-59C>T	upstream_gene_variant	ENST00000375949.5	NP_009203.2	Q99895
CTRC	XM_011540550.2 linkuse as main transcript	c.-59C>T	upstream_gene_variant		XP_011538852.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CTRC	ENST00000375949.5 linkuse as main transcript	c.-59C>T	upstream_gene_variant	1	NM_007272.3	ENSP00000365116.4	Q99895
CTRC	ENST00000375943.6 linkuse as main transcript	c.-59C>T	upstream_gene_variant	1		ENSP00000365110.2	Q68DR9
CTRC	ENST00000476813.5 linkuse as main transcript	n.-47C>T	upstream_gene_variant	3

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.00216

AC:

3130

AN:

1452362

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1524

AN XY:

723316

show subpopulations

Gnomad4 AFR exome

AF:

0.000811

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00254

Gnomad4 OTH exome

AF:

0.00185

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152314

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00313

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00214

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 23, 2023	The CTRC c.-59C>T variant (rs183658182) has been reported in pancreatitis patients (Ballard 2015, Masson 2008), but not at a significantly higher frequency compared to unaffected individuals. This variant is found in the non-Finnish European population with an allele frequency of 0.337% (52/15,428 alleles) in the Genome Aggregation Database. This variant occurs in the 5' untranslated region at a nucleotide that is weakly conserved and does not create a novel protein translation start codon. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ballard DD et al. Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing. Pancreas. 2015 Jan;44(1):116-21. PMID: 25251442. Masson E et al. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. PMID: 18172691. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 06, 2021	- -

CTRC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The CTRC c.-59C>T variant is located in the 5' untranslated region. This variant was reported in four individuals with idiopathic chronic pancreatitis, one individual with familial chronic pancreatitis, and one individual with hereditary pancreatitis but was also found in two controls (Table 4, Masson et al. 2008. PubMed ID: 18172691). This variant was also reported in two individuals with unexplained pancreatitis, although one individual also carried a CFTR variant (Supplementary Table, Ballard et al. 2015. PubMed ID: 25251442). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual, and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/240761/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

DANN

Benign

0.66

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over