7-130380524-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001868.4(CPA1):c.4C>T(p.Arg2Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000837 in 1,314,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

CPA1
NM_001868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.883

Variant links:

Genes affected

CPA1 (HGNC:2296): (carboxypeptidase A1) This gene encodes a member of the carboxypeptidase A family of zinc metalloproteases. This enzyme is produced in the pancreas and preferentially cleaves C-terminal branched-chain and aromatic amino acids from dietary proteins. This gene and several family members are present in a gene cluster on chromosome 7. Mutations in this gene may be linked to chronic pancreatitis, while elevated protein levels may be associated with pancreatic cancer. [provided by RefSeq, Jan 2015]

CPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.23435965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA1	NM_001868.4 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 10	ENST00000011292.8	NP_001859.1	P15085

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPA1	ENST00000011292.8 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 10	1	NM_001868.4	ENSP00000011292.3	P15085
CPA1	ENST00000604896.5 link	c.4C>T	p.Arg2Trp	missense_variant	Exon 1 of 6	3		ENSP00000475021.2	S4R433
CPA1	ENST00000481342.5 link	c.-200+115C>T		intron_variant	Intron 1 of 4	3		ENSP00000420218.1	C9JQ63
CPA1	ENST00000491460.5 link	n.31C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000774

AC:

AN:

1162508

Hom.:

Cov.:

AF XY:

0.00000898

AC XY:

AN XY:

556958

show subpopulations

Gnomad4 AFR exome

AF:

0.0000401

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000327

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000248

Gnomad4 NFE exome

AF:

0.00000628

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2W variant (also known as c.4C>T), located in coding exon 1 of the CPA1 gene, results from a C to T substitution at nucleotide position 4. The arginine at codon 2 is replaced by tryptophan, an amino acid with dissimilar 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. -

not provided

Uncertain:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2 of the CPA1 protein (p.Arg2Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1000164). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.69

D;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Benign

0.10

Sift

Benign

0.077

T;.

Sift4G

Benign

0.063

T;D

Polyphen

0.98

D;.

Vest4

0.21

MutPred

0.53

Loss of disorder (P = 8e-04);.;

MVP

0.41

MPC

0.37

ClinPred

0.44

GERP RS

-3.6

Varity_R

0.14

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

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