rs2295766

Positions:

chr6-2953160-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004568.6(SERPINB6):c.457G>A(p.Gly153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,614,204 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00088 ( 13 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.853

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=0.0077928305).

BP6

Variant 6-2953160-C-T is Benign according to our data. Variant chr6-2953160-C-T is described in ClinVar as [Benign]. Clinvar id is 44134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (178/152320) while in subpopulation EAS AF= 0.0193 (100/5186). AF 95% confidence interval is 0.0162. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.457G>A	p.Gly153Ser	missense_variant	5/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7 linkuse as main transcript	c.457G>A	p.Gly153Ser	missense_variant	5/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00408

AC:

1025

AN:

251480

Hom.:

AF XY:

0.00308

AC XY:

418

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0221

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.000876

AC:

1280

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000729

AC XY:

530

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0114

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152320

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00444

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000699

Hom.:

Bravo

AF:

0.00195

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00335

AC:

407

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Gly153Ser in Exon 06 of SERPINB6: This variant is not expected to have clinical significance because it has been identified in 5.0% (5/100) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs 2295766). -

SERPINB6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

4.7

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.50

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

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.76

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

MetaRNN

Benign

0.0078

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

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.4

M;M;M;M;M;M;M;.;.;.;M;M;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.18

Sift

Benign

0.045

D;D;D;D;.;D;.;.;.;.;.;D;.;.

Sift4G

Uncertain

0.058

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

Polyphen

0.030

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

Vest4

0.15

MVP

0.88

MPC

0.30

ClinPred

0.028

GERP RS

0.012

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.40

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