Genetic Variant NM_002575.3:c.358A>G (chr18-63897160-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_002575.3(SERPINB2):c.358A>G(p.Asn120Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,611,998 control chromosomes in the GnomAD database, including 51,138 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 0.29 ( 6841 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44297 hom. )

Consequence

SERPINB2
NM_002575.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.809

Publications

38 publications found

Variant links:

Genes affected

SERPINB2 (HGNC:8584): (serpin family B member 2) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINB2 links:

ENSG00000289724 (HGNC:):

ENSG00000289724 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.001850158).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3 link	c.358A>G	p.Asn120Asp	missense_variant	Exon 4 of 8	ENST00000299502.9	NP_002566.1	P05120
SERPINB2	NM_001143818.2 link	c.358A>G	p.Asn120Asp	missense_variant	Exon 5 of 9		NP_001137290.1	P05120
SERPINB2	XM_024451192.2 link	c.358A>G	p.Asn120Asp	missense_variant	Exon 4 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9 link	c.358A>G	p.Asn120Asp	missense_variant	Exon 4 of 8	1	NM_002575.3	ENSP00000299502.4		P05120
ENSG00000289724	ENST00000418725.1 link	c.-15A>G		upstream_gene_variant		5		ENSP00000392381.1		H7C004

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43494

AN:

151964

Hom.:

6820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.363

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.479

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.304

GnomAD2 exomes

AF:

0.284

AC:

71089

AN:

250042

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.368

Gnomad AMR exome

AF:

0.425

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.471

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.239

AC:

349163

AN:

1459916

Hom.:

44297

Cov.:

AF XY:

0.240

AC XY:

173944

AN XY:

726276

show subpopulations

African (AFR)

AF:

0.370

AC:

12342

AN:

33386

American (AMR)

AF:

0.414

AC:

18385

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4860

AN:

26072

East Asian (EAS)

AF:

0.404

AC:

15990

AN:

39592

South Asian (SAS)

AF:

0.279

AC:

23994

AN:

85970

European-Finnish (FIN)

AF:

0.228

AC:

12157

AN:

53358

Middle Eastern (MID)

AF:

0.302

AC:

1737

AN:

5752

European-Non Finnish (NFE)

AF:

0.220

AC:

244024

AN:

1111052

Other (OTH)

AF:

0.260

AC:

15674

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

12364

24727

37091

49454

61818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8696

17392

26088

34784

43480

<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:

0.286

AC:

43550

AN:

152082

Hom.:

6841

Cov.:

AF XY:

0.290

AC XY:

21525

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.363

AC:

15066

AN:

41490

American (AMR)

AF:

0.370

AC:

5659

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.184

AC:

638

AN:

3468

East Asian (EAS)

AF:

0.479

AC:

2475

AN:

5166

South Asian (SAS)

AF:

0.297

AC:

1432

AN:

4814

European-Finnish (FIN)

AF:

0.233

AC:

2466

AN:

10566

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.220

AC:

14943

AN:

67980

Other (OTH)

AF:

0.310

AC:

653

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1548

3097

4645

6194

7742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.243

Hom.:

19614

Bravo

AF:

0.302

TwinsUK

AF:

0.202

AC:

748

ALSPAC

AF:

0.208

AC:

803

ESP6500AA

AF:

0.369

AC:

1626

ESP6500EA

AF:

0.218

AC:

1878

ExAC

AF:

0.279

AC:

33823

Asia WGS

AF:

0.389

AC:

1350

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.224

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.10

T;T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.028

.;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

N;N;.;.

PhyloP100

0.81

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.060

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.80

T;T;T;T

Sift4G

Benign

0.67

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.017

MPC

0.016

ClinPred

0.0026

GERP RS

4.1

PromoterAI

-0.0066

Neutral

(source)

Varity_R

0.17

gMVP

0.084

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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