rs2295769

Positions:

chr6-2955568-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.268A>G	p.Met90Val	missense_variant	3/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7 linkuse as main transcript	c.268A>G	p.Met90Val	missense_variant	3/7	3	NM_004568.6	P1

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

GnomAD3 exomes

AF:

0.266

AC:

66825

AN:

251472

Hom.:

9577

AF XY:

0.275

AC XY:

37381

AN XY:

135904

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 SAS exome

AF:

0.311

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

Gnomad4 AFR exome

AF:

0.0639

Gnomad4 AMR exome

AF:

0.220

Gnomad4 ASJ exome

AF:

0.327

Gnomad4 EAS exome

AF:

0.264

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.239

Gnomad4 NFE exome

AF:

0.304

Gnomad4 OTH exome

AF:

0.288

GnomAD4 genome

AF:

0.227

AC:

34598

AN:

152190

Hom.:

4689

Cov.:

AF XY:

0.227

AC XY:

16893

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0708

Gnomad4 AMR

AF:

0.264

Gnomad4 ASJ

AF:

0.327

Gnomad4 EAS

AF:

0.267

Gnomad4 SAS

AF:

0.289

Gnomad4 FIN

AF:

0.229

Gnomad4 NFE

AF:

0.301

Gnomad4 OTH

AF:

0.239

Alfa

AF:

0.290

Hom.:

17174

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 91

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

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;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over