Genetic Variant SERPINB2:p.Arg229His (chr18-63902411-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002575.3(SERPINB2):c.686G>A(p.Arg229His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,597,266 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

SERPINB2
NM_002575.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.157

Publications

27 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041959584).

BP6

Variant 18-63902411-G-A is Benign according to our data. Variant chr18-63902411-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 728330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002575.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB2	NM_002575.3	MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 8	NP_002566.1	P05120
	SERPINB2	NM_001143818.2		c.686G>A	p.Arg229His	missense	Exon 8 of 9	NP_001137290.1	P05120

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINB2	ENST00000299502.9	TSL:1 MANE Select	c.686G>A	p.Arg229His	missense	Exon 7 of 8	ENSP00000299502.4	P05120
ENSG00000289724	ENST00000418725.1	TSL:5	c.314G>A	p.Arg105His	missense	Exon 4 of 7	ENSP00000392381.1	H7C004
SERPINB2	ENST00000457692.5	TSL:5	c.686G>A	p.Arg229His	missense	Exon 8 of 9	ENSP00000401645.1	P05120

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00143

AC:

344

AN:

240504

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.000760

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.000208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00276

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.00138

GnomAD4 exome

AF:

0.00146

AC:

2104

AN:

1445108

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1094

AN XY:

718106

show subpopulations

African (AFR)

AF:

0.000825

AC:

AN:

32716

American (AMR)

AF:

0.000736

AC:

AN:

42148

Ashkenazi Jewish (ASJ)

AF:

0.000118

AC:

AN:

25508

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83418

European-Finnish (FIN)

AF:

0.00347

AC:

184

AN:

53058

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00163

AC:

1797

AN:

1103610

Other (OTH)

AF:

0.000989

AC:

AN:

59646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.00197

AC:

299

AN:

152158

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

41534

American (AMR)

AF:

0.000524

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00263

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00137

AC:

166

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.27

M_CAP

Benign

0.035

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.58

PhyloP100

-0.16

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.0

REVEL

Benign

0.082

Sift

Benign

0.20

Sift4G

Benign

0.12

Polyphen

0.038

Vest4

0.043

MVP

0.44

MPC

0.016

ClinPred

0.0026

GERP RS

1.2

Varity_R

0.058

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over