7-130380523-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001868.4(CPA1):c.3G>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPA1 NM_001868.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA1	NM_001868.4	c.3G>T	p.Met1?	start_lost	1/10	ENST00000011292.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA1	ENST00000011292.8	c.3G>T	p.Met1?	start_lost	1/10	1	NM_001868.4	P1
CPA1	ENST00000604896.5	c.3G>T	p.Met1?	start_lost	1/6	3
CPA1	ENST00000481342.5	c.-200+114G>T		intron_variant		3
CPA1	ENST00000491460.5	n.30G>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1162990 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 557194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

This sequence change affects the initiator methionine of the CPA1 mRNA. The next in-frame methionine is located at codon 89. 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. 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
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;T
Polyphen		0.92	P;.
Vest4		0.80
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0107);.;
MVP		0.50
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.68
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-130020364;