rs200576965

Variant names:

• chr1-15440311-G-A
• rs200576965
• NM_007272.3:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BS2_Supporting

The NM_007272.3(CTRC):​c.52G>A​(p.Gly18Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,585,500 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G18G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.52
• Publications: 1 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 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• BS2: High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.52G>A	p.Gly18Arg	missense	Exon 2 of 8	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.52G>A	p.Gly18Arg	missense	Exon 2 of 8	ENSP00000365116.4	Q99895
	CTRC	ENST00000375943.6	TSL:1	c.40+1807G>A		intron	N/A	ENSP00000365110.2	Q68DR9
	CTRC	ENST00000476813.5	TSL:3	n.52+1807G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000471 AC: 7 AN: 148652 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000683

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000623 AC: 15 AN: 240852 AF XY: 0.0000458

Gnomad AFR exome AF: 0.0000689

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 152 AN: 1436848 Hom.: 0 Cov.: 35 AF XY: 0.0000994 AC XY: 71 AN XY: 714068

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.00 AC: 0 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25210

East Asian (EAS) AF: 0.00 AC: 0 AN: 38472

South Asian (SAS) AF: 0.00 AC: 0 AN: 84944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4298

European-Non Finnish (NFE) AF: 0.000135 AC: 148 AN: 1097874

Other (OTH) AF: 0.0000682 AC: 4 AN: 58652

GnomAD4 genome AF: 0.0000471 AC: 7 AN: 148652 Hom.: 0 Cov.: 31 AF XY: 0.0000415 AC XY: 3 AN XY: 72278

African (AFR) AF: 0.0000496 AC: 2 AN: 40348

American (AMR) AF: 0.0000683 AC: 1 AN: 14650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000592 AC: 4 AN: 67558

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000907 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Hereditary pancreatitis (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.60		Gain of solvent accessibility (P = 0.0471)
MVP		0.97
MPC		0.80
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.88
gMVP		0.64
Mutation Taster		=47/53	disease causing

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: rs200576965; hg19: chr1-15766807;