rs61737420

Positions:

chr6-2948393-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004568.6(SERPINB6):c.1036G>A(p.Val346Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000753 in 1,614,132 control chromosomes in the GnomAD database, including 7 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 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -4.06

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:

SERPINB6 (HGNC:):

SERPINB6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005579382).

BP6

Variant 6-2948393-C-T is Benign according to our data. Variant chr6-2948393-C-T is described in ClinVar as [Benign]. Clinvar id is 44130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-2948393-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.1036G>A	p.Val346Ile	missense_variant	7/7	ENST00000380539.7	NP_004559.4	P35237A0A024QZX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7 linkuse as main transcript	c.1036G>A	p.Val346Ile	missense_variant	7/7	3	NM_004568.6	ENSP00000369912.2		P35237

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

553

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000943

AC:

237

AN:

251354

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0118

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000454

AC:

663

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000410

AC XY:

298

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0115

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00363

AC:

553

AN:

152250

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

257

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0125

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000699

Hom.:

Bravo

AF:

0.00410

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Val346Ile in Exon 08 of SERPINB6: This variant is not expected to have clinical significance because it has been identified in 1.3% (48/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs61737420). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.012

DANN

Benign

0.82

DEOGEN2

Benign

0.14

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

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.038

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

MetaRNN

Benign

0.0056

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

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.57

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

REVEL

Benign

0.21

Sift

Benign

0.45

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

Sift4G

Benign

0.20

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

Polyphen

0.0020

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

Vest4

0.065

MVP

0.41

MPC

0.079

ClinPred

0.0063

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.030

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