Genetic Variant SERPINB10:p.Arg246Cys (chr18-63933150-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005024.3(SERPINB10):c.736C>T(p.Arg246Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,612,928 control chromosomes in the GnomAD database, including 80,816 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R246H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.41 ( 15789 hom., cov: 32)

Exomes 𝑓: 0.29 ( 65027 hom. )

Consequence

SERPINB10
NM_005024.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0430

Publications

39 publications found

Variant links:

Genes affected

SERPINB10 (HGNC:8942): (serpin family B member 10) This gene is a member of the serpin peptidase inhibitor, clade B family and is found in a cluster of other similar genes on chromosome 18. The protein encoded by this gene appears to help control the regulation of protease functions during hematopoiesis. Variations in this gene may increase the risk of prostate cancer. [provided by RefSeq, Dec 2015]

SERPINB10 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=1.3115061E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB10	NM_005024.3 link	c.736C>T	p.Arg246Cys	missense_variant	Exon 7 of 8	ENST00000238508.8	NP_005015.1	P48595B2RC45
SERPINB10	XM_011526027.2 link	c.736C>T	p.Arg246Cys	missense_variant	Exon 8 of 9		XP_011524329.1	P48595
SERPINB10	XM_017025793.2 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 8		XP_016881282.1
SERPINB10	XM_011526028.1 link	c.349C>T	p.Arg117Cys	missense_variant	Exon 5 of 6		XP_011524330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB10	ENST00000238508.8 link	c.736C>T	p.Arg246Cys	missense_variant	Exon 7 of 8	1	NM_005024.3	ENSP00000238508.3		P48595

Frequencies

GnomAD3 genomes

AF:

0.412

AC:

62546

AN:

151860

Hom.:

15746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.708

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.394

GnomAD2 exomes

AF:

0.337

AC:

84627

AN:

251276

AF XY:

0.322

show subpopulations

Gnomad AFR exome

AF:

0.717

Gnomad AMR exome

AF:

0.458

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.303

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.287

AC:

419302

AN:

1460950

Hom.:

65027

Cov.:

AF XY:

0.285

AC XY:

207235

AN XY:

726828

show subpopulations

African (AFR)

AF:

0.724

AC:

24224

AN:

33448

American (AMR)

AF:

0.449

AC:

20045

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

4822

AN:

26126

East Asian (EAS)

AF:

0.386

AC:

15308

AN:

39682

South Asian (SAS)

AF:

0.294

AC:

25312

AN:

86226

European-Finnish (FIN)

AF:

0.298

AC:

15892

AN:

53412

Middle Eastern (MID)

AF:

0.325

AC:

1877

AN:

5768

European-Non Finnish (NFE)

AF:

0.264

AC:

292855

AN:

1111256

Other (OTH)

AF:

0.314

AC:

18967

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

15937

31874

47812

63749

79686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10152

20304

30456

40608

50760

<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:

0.412

AC:

62648

AN:

151978

Hom.:

15789

Cov.:

AF XY:

0.412

AC XY:

30569

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.708

AC:

29355

AN:

41454

American (AMR)

AF:

0.423

AC:

6456

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

619

AN:

3470

East Asian (EAS)

AF:

0.439

AC:

2269

AN:

5168

South Asian (SAS)

AF:

0.305

AC:

1472

AN:

4820

European-Finnish (FIN)

AF:

0.305

AC:

3209

AN:

10536

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.267

AC:

18166

AN:

67956

Other (OTH)

AF:

0.399

AC:

842

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1623

3246

4868

6491

8114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.311

Hom.:

29748

Bravo

AF:

0.436

TwinsUK

AF:

0.249

AC:

923

ALSPAC

AF:

0.254

AC:

979

ESP6500AA

AF:

0.695

AC:

3064

ESP6500EA

AF:

0.259

AC:

2224

ExAC

AF:

0.336

AC:

40772

Asia WGS

AF:

0.410

AC:

1425

AN:

3478

EpiCase

AF:

0.270

EpiControl

AF:

0.267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.20

.;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

-0.043

PROVEAN

Uncertain

-3.6

D;.

REVEL

Benign

0.19

Sift

Benign

0.066

T;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.068

B;B

Vest4

0.057

MPC

0.021

ClinPred

0.026

GERP RS

0.68

Varity_R

0.14

gMVP

0.49

Mutation Taster

=99/1

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