7-130380524-C-T

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

1
1
17

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]

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
CPA1NM_001868.4 linkc.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 Appris UniProt
CPA1ENST00000011292.8 linkc.4C>T p.Arg2Trp missense_variant Exon 1 of 10 1 NM_001868.4 ENSP00000011292.3 P15085
CPA1ENST00000604896.5 linkc.4C>T p.Arg2Trp missense_variant Exon 1 of 6 3 ENSP00000475021.2 S4R433
CPA1ENST00000481342.5 linkc.-200+115C>T intron_variant Intron 1 of 4 3 ENSP00000420218.1 C9JQ63
CPA1ENST00000491460.5 linkn.31C>T non_coding_transcript_exon_variant Exon 1 of 6 2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
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:
9
AN:
1162508
Hom.:
0
Cov.:
29
AF XY:
0.00000898
AC XY:
5
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:
2
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
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
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
15
DANN
Benign
0.95
DEOGEN2
Uncertain
0.69
D;T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.070
N
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.0091
T
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.24
T
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
T
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.

Other links and lift over

dbSNP: rs541913287; hg19: chr7-130020365; COSMIC: COSV50569921; COSMIC: COSV50569921; API