rs145538358

Positions:

chr6-2959233-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004568.6(SERPINB6):c.100A>G(p.Met34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,200 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000082 ( 1 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.99

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015023053).

BP6

Variant 6-2959233-T-C is Benign according to our data. Variant chr6-2959233-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227935.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.100A>G	p.Met34Val	missense_variant	2/7	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.100A>G	p.Met34Val	missense_variant	2/7	3	NM_004568.6	ENSP00000369912	P1

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251492

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00209

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152306

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00260

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2015

p.Met34Val in exon 3 of SERPINB6: This variant is not expected to have clinical significance because it has been identified in 0.25% (26/10406) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs145538358). In addition, methionine (Met) at this position is poorly c onserved across many mammals and all evolutionarily distant species, and computa tional tools do not predict an impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.021

MetaRNN

Benign

0.015

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.68

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

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.58

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

REVEL

Benign

0.23

Sift

Benign

0.054

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

Sift4G

Uncertain

0.047

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

Polyphen

0.0

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

Vest4

0.25

MVP

0.55

MPC

0.099

ClinPred

0.017

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.078

gMVP

0.079

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