Genetic Variant NM_080385.5:c.1007T>C (chr7-130367540-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_080385.5(CPA5):c.1007T>C(p.Leu336Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,612,920 control chromosomes in the GnomAD database, including 37,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 5198 hom., cov: 32)

Exomes 𝑓: 0.20 ( 31857 hom. )

Consequence

CPA5
NM_080385.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

27 publications found

Variant links:

Genes affected

CPA5 (HGNC:15722): (carboxypeptidase A5) Carboxypeptidases have functions ranging from digestion of food to selective biosynthesis of neuroendocrine peptides. Members of the A/B subfamily of carboxypeptidases, such as CPA5, contain an approximately 90-amino acid pro region that assists in the folding of the active carboxypeptidase domain. Cleavage of the pro region activates the enzyme (Wei et al., 2002 [PubMed 11836249]).[supplied by OMIM, Mar 2008]

CPA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040917993).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA5	NM_080385.5 link	c.1007T>C	p.Leu336Ser	missense_variant	Exon 11 of 13	ENST00000474905.6	NP_525124.3	Q8WXQ8-1A4D1M2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA5	ENST00000474905.6 link	c.1007T>C	p.Leu336Ser	missense_variant	Exon 11 of 13	1	NM_080385.5	ENSP00000417314.1		Q8WXQ8-1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37057

AN:

151846

Hom.:

5184

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.0256

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.213

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.186

AC:

46870

AN:

251464

AF XY:

0.185

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.107

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.0268

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.202

AC:

295307

AN:

1460956

Hom.:

31857

Cov.:

AF XY:

0.200

AC XY:

145412

AN XY:

726828

show subpopulations

African (AFR)

AF:

0.380

AC:

12709

AN:

33458

American (AMR)

AF:

0.112

AC:

5030

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5318

AN:

26124

East Asian (EAS)

AF:

0.0230

AC:

914

AN:

39698

South Asian (SAS)

AF:

0.136

AC:

11688

AN:

86248

European-Finnish (FIN)

AF:

0.202

AC:

10812

AN:

53416

Middle Eastern (MID)

AF:

0.257

AC:

1481

AN:

5758

European-Non Finnish (NFE)

AF:

0.211

AC:

234935

AN:

1111166

Other (OTH)

AF:

0.206

AC:

12420

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

11883

23766

35649

47532

59415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8004

16008

24012

32016

40020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.244

AC:

37099

AN:

151964

Hom.:

5198

Cov.:

AF XY:

0.238

AC XY:

17660

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.379

AC:

15684

AN:

41398

American (AMR)

AF:

0.169

AC:

2584

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

711

AN:

3470

East Asian (EAS)

AF:

0.0255

AC:

132

AN:

5174

South Asian (SAS)

AF:

0.136

AC:

653

AN:

4810

European-Finnish (FIN)

AF:

0.203

AC:

2152

AN:

10584

Middle Eastern (MID)

AF:

0.253

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.213

AC:

14504

AN:

67958

Other (OTH)

AF:

0.231

AC:

487

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1377

2755

4132

5510

6887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.217

Hom.:

15396

Bravo

AF:

0.247

TwinsUK

AF:

0.206

AC:

762

ALSPAC

AF:

0.210

AC:

811

ESP6500AA

AF:

0.379

AC:

1672

ESP6500EA

AF:

0.216

AC:

1854

ExAC

AF:

0.197

AC:

23871

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0086

T;T;T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.014

.;.;.;T;.;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.4

N;N;N;N;N;N

PhyloP100

1.2

PrimateAI

Benign

0.28

PROVEAN

Benign

2.4

N;N;N;N;N;N

REVEL

Benign

0.080

Sift

Benign

0.41

T;T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T;T

Polyphen

0.0

B;B;B;.;B;B

Vest4

0.028

MPC

0.24

ClinPred

0.0049

GERP RS

3.7

Varity_R

0.033

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over