rs2171492

chr7-130310900-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016352.4(CPA4):c.907G>T(p.Gly303Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,613,408 control chromosomes in the GnomAD database, including 110,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (8671 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102065 hom.)
• Consequence: CPA4 NM_016352.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180

Genes affected

CPA4 (HGNC:15740): (carboxypeptidase A4) This gene is a member of the carboxypeptidase A/B subfamily, and it is located in a cluster with three other family members on chromosome 7. Carboxypeptidases are zinc-containing exopeptidases that catalyze the release of carboxy-terminal amino acids, and are synthesized as zymogens that are activated by proteolytic cleavage. This gene could be involved in the histone hyperacetylation pathway. It is imprinted and may be a strong candidate gene for prostate cancer aggressiveness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008575439).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPA4	NM_016352.4	c.907G>T	p.Gly303Cys	missense_variant	9/11	ENST00000222482.10
CPA4	NM_001163446.2	c.808G>T	p.Gly270Cys	missense_variant	8/10
CPA4	XM_047420438.1	c.595G>T	p.Gly199Cys	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPA4	ENST00000222482.10	c.907G>T	p.Gly303Cys	missense_variant	9/11	1	NM_016352.4	P1
CPA4	ENST00000445470.6	c.808G>T	p.Gly270Cys	missense_variant	8/10	2
CPA4	ENST00000493259.5	c.595G>T	p.Gly199Cys	missense_variant	7/9	2
CPA4	ENST00000488025.1	n.380G>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50351 AN: 151896 Hom.: 8672 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.339

GnomAD3 exomes AF: 0.349 AC: 87711 AN: 251456 Hom.: 15768 AF XY: 0.356 AC XY: 48340 AN XY: 135900

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.376

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.372 AC: 543491 AN: 1461394 Hom.: 102065 Cov.: 38 AF XY: 0.372 AC XY: 270456 AN XY: 727040

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.349

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.331 AC: 50366 AN: 152014 Hom.: 8671 Cov.: 32 AF XY: 0.332 AC XY: 24651 AN XY: 74302

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.357

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.335

Alfa AF: 0.375 Hom.: 27083

Bravo AF: 0.322

TwinsUK AF: 0.389 AC: 1442

ALSPAC AF: 0.384 AC: 1481

ESP6500AA AF: 0.228 AC: 1003

ESP6500EA AF: 0.385 AC: 3310

ExAC AF: 0.348 AC: 42227

Asia WGS AF: 0.388 AC: 1350 AN: 3478

EpiCase AF: 0.390

EpiControl AF: 0.384

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.032	T;.;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.0086	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.060	N;.;.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
Polyphen		0.0040	B;.;.;B
Vest4		0.16, 0.085, 0.13
MPC		0.12
ClinPred		0.0069	T
GERP RS		0.48
Varity_R		0.43
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs2171492; hg19: chr7-129950740; COSMIC: COSV55982488; COSMIC: COSV55982488;