rs140220538

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004568.6(SERPINB6):c.121G>A(p.Val41Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00056 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 2 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.02

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036459863).

BP6

Variant 6-2959212-C-T is Benign according to our data. Variant chr6-2959212-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr6-2959212-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB6	NM_004568.6 link	c.121G>A	p.Val41Ile	missense_variant	Exon 2 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.121G>A	p.Val41Ile	missense_variant	Exon 2 of 7	3	NM_004568.6	ENSP00000369912.2		P35237

Frequencies

GnomAD3 genomes

AF:

0.000558

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000473

AC:

119

AN:

251494

Hom.:

AF XY:

0.000522

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000378

AC:

553

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000321

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000558

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000554

Hom.:

Bravo

AF:

0.000654

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 91

Uncertain:1

Feb 08, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Apr 11, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val41Ile in exon 2C of SERPINB6: This variant is classified as likely benign b ecause it has been identified in 0.3% (29/10152) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs140220538). ACMG/AMP Criteria applied: BS1 -

SERPINB6-related disorder

Benign:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.036

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

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.5

L;L;L;L;L;L;L;.;.;L;L;.;.;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.72

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

REVEL

Uncertain

0.43

Sift

Benign

0.054

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

Sift4G

Benign

0.090

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

Polyphen

0.74

P;P;P;P;P;P;P;.;.;P;P;.;.;.;.;.

Vest4

0.10

MVP

0.71

MPC

0.30

ClinPred

0.064

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.19

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