NM_007272.3:c.-59C>T

Variant names:

• chr1-15438406-C-T
• rs183658182
• NM_007272.3:c.-59C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007272.3(CTRC):​c.-59C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. 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: CTRC NM_007272.3 upstream_gene
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: -0.0920
• Publications: 2 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: Benign. The variant received -13 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 VariationId is 240761.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00215 (327/152314) while in subpopulation AMR AF = 0.00536 (82/15298). AF 95% confidence interval is 0.00442. There are 2 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 327 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007272.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRC	NM_007272.3	MANE Select	c.-59C>T		upstream_gene	N/A	NP_009203.2	Q99895

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRC	ENST00000375949.5	TSL:1 MANE Select	c.-59C>T		upstream_gene	N/A	ENSP00000365116.4	Q99895
	CTRC	ENST00000375943.6	TSL:1	c.-59C>T		upstream_gene	N/A	ENSP00000365110.2	Q68DR9
	CTRC	ENST00000476813.5	TSL:3	n.-47C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152196 Hom.: 2 Cov.: 32

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.: 5 Cov.: 30 AF XY: 0.00211 AC XY: 1524 AN XY: 723316

African (AFR) AF: 0.000811 AC: 27 AN: 33294

American (AMR) AF: 0.00333 AC: 149 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86016

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53354

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.00254 AC: 2808 AN: 1103446

Other (OTH) AF: 0.00185 AC: 111 AN: 60052

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74482

African (AFR) AF: 0.000553 AC: 23 AN: 41566

American (AMR) AF: 0.00536 AC: 82 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00313 AC: 213 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00214

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	Hereditary pancreatitis (4)
-	1	1	not provided (2)
-	1	-	CTRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.66
PhyloP100		-0.092
PromoterAI		0.0060	Neutral

Splicing

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

Other links and lift over

dbSNP: rs183658182; hg19: chr1-15764902;