7-130273100-G-A

Variant names:

• chr7-130273100-G-A
• rs748413926
• NM_001869.3:c.409G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001869.3(CPA2):​c.409G>A​(p.Val137Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPA2 NM_001869.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

CPA2 (HGNC:2297): (carboxypeptidase A2) Three different forms of human pancreatic procarboxypeptidase A have been isolated. The encoded protein represents the A2 form, which is a monomeric protein with different biochemical properties from the A1 and A3 forms. The A2 form of pancreatic procarboxypeptidase acts on aromatic C-terminal residues and is a secreted protein. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA2	NM_001869.3	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 11	ENST00000222481.9	NP_001860.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA2	ENST00000222481.9	c.409G>A	p.Val137Met	missense_variant	Exon 5 of 11	1	NM_001869.3	ENSP00000222481.4
CPA2	ENST00000416698.1	n.403G>A		non_coding_transcript_exon_variant	Exon 5 of 8	5		ENSP00000395582.1
CPA2	ENST00000480781.5	n.426G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2
CPA2	ENST00000487259.5	n.424G>A		non_coding_transcript_exon_variant	Exon 5 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409G>A (p.V137M) alteration is located in exon 5 (coding exon 5) of the CPA2 gene. This alteration results from a G to A substitution at nucleotide position 409, causing the valine (V) at amino acid position 137 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.077	T
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.66		Gain of disorder (P = 0.055);
MVP		0.53
MPC		0.45
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.54
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs748413926; hg19: chr7-129912940;