rs374321672

Positions:

chr6-2948584-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004568.6(SERPINB6):c.845T>C(p.Met282Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.03

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.845T>C	p.Met282Thr	missense_variant	7/7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7 linkuse as main transcript	c.845T>C	p.Met282Thr	missense_variant	7/7	3	NM_004568.6	ENSP00000369912	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 16, 2016

The p.Met282Thr variant in SERPINB6 has not been previously reported in individu als with hearing loss, but has been identified in 1/11578 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 374321672). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. Methionine (Met) at p osition 282 is not conserved in mammals or evolutionarily distant species, raisi ng the possibility that a change at this position may be tolerated. Additional c omputational prediction tools do not provide strong support for or against an im pact to the protein. In summary, the clinical significance of the p.Met282Thr va riant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.68

D;D;D;D;D;D;D;T;T;.;D;D;T

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Pathogenic

3.2

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.6

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

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.96

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

Vest4

0.63

MVP

0.92

MPC

0.48

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.96

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