rs2295769

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004568.6(SERPINB6):c.268A>G(p.Met90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,874 control chromosomes in the GnomAD database, including 68,999 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4689 hom., cov: 33)

Exomes 𝑓: 0.29 ( 64310 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.23

Publications

44 publications found

Variant links:

Genes affected

SERPINB6 (HGNC:8950): (serpin family B member 6) The protein encoded by this gene is a member of the serpin (serine proteinase inhibitor) superfamily, and ovalbumin(ov)-serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

SERPINB6 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 91
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SERPINB6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016168445).

BP6

Variant 6-2955568-T-C is Benign according to our data. Variant chr6-2955568-T-C is described in ClinVar as Benign. ClinVar VariationId is 44132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB6	NM_004568.6 link	c.268A>G	p.Met90Val	missense_variant	Exon 3 of 7	ENST00000380539.7	NP_004559.4	P35237A0A024QZX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7 link	c.268A>G	p.Met90Val	missense_variant	Exon 3 of 7	3	NM_004568.6	ENSP00000369912.2		P35237

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34590

AN:

152072

Hom.:

4682

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0709

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.234

GnomAD2 exomes

AF:

0.266

AC:

66825

AN:

251472

AF XY:

0.275

show subpopulations

Gnomad AFR exome

AF:

0.0634

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.261

Gnomad FIN exome

AF:

0.237

Gnomad NFE exome

AF:

0.298

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.292

AC:

427371

AN:

1461684

Hom.:

64310

Cov.:

AF XY:

0.294

AC XY:

213967

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0639

AC:

2138

AN:

33472

American (AMR)

AF:

0.220

AC:

9822

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

8538

AN:

26134

East Asian (EAS)

AF:

0.264

AC:

10481

AN:

39700

South Asian (SAS)

AF:

0.307

AC:

26511

AN:

86248

European-Finnish (FIN)

AF:

0.239

AC:

12769

AN:

53412

Middle Eastern (MID)

AF:

0.327

AC:

1886

AN:

5766

European-Non Finnish (NFE)

AF:

0.304

AC:

337825

AN:

1111838

Other (OTH)

AF:

0.288

AC:

17401

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

16937

33875

50812

67750

84687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11004

22008

33012

44016

55020

<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:

0.227

AC:

34598

AN:

152190

Hom.:

4689

Cov.:

AF XY:

0.227

AC XY:

16893

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0708

AC:

2941

AN:

41524

American (AMR)

AF:

0.264

AC:

4031

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1135

AN:

3470

East Asian (EAS)

AF:

0.267

AC:

1383

AN:

5178

South Asian (SAS)

AF:

0.289

AC:

1394

AN:

4830

European-Finnish (FIN)

AF:

0.229

AC:

2418

AN:

10582

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.301

AC:

20444

AN:

67996

Other (OTH)

AF:

0.239

AC:

505

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1327

2654

3980

5307

6634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.277

Hom.:

23913

Bravo

AF:

0.220

TwinsUK

AF:

0.318

AC:

1179

ALSPAC

AF:

0.302

AC:

1162

ESP6500AA

AF:

0.0660

AC:

291

ESP6500EA

AF:

0.299

AC:

2574

ExAC

AF:

0.264

AC:

32100

Asia WGS

AF:

0.275

AC:

957

AN:

3478

EpiCase

AF:

0.309

EpiControl

AF:

0.303

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Met90Val in Exon 04 of SERPINB6: This variant is not expected to have clinical s ignificance because it has been identified in 30.0% (2104/7020) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2295769). -

Autosomal recessive nonsyndromic hearing loss 91

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.11

T;T;T;T;T;T;T;T;T;.;T;T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.63

.;.;.;.;.;.;.;T;.;T;.;T;T;T;.

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

N;N;N;N;N;N;N;.;.;.;N;N;.;.;.

PhyloP100

2.2

PrimateAI

Benign

0.23

PROVEAN

Benign

0.35

N;N;N;N;.;N;.;.;.;.;.;N;.;.;.

REVEL

Benign

0.19

Sift

Benign

1.0

T;T;T;T;.;T;.;.;.;.;.;T;.;.;.

Sift4G

Benign

1.0

T;T;T;T;.;T;.;T;.;.;.;T;.;.;.

Polyphen

0.0

B;B;B;B;B;B;B;.;.;.;B;B;.;.;.

Vest4

0.016

MPC

0.097

ClinPred

0.0083

GERP RS

3.8

Varity_R

0.067

gMVP

0.17

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over