6-2948483-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004568.6(SERPINB6):c.946G>A(p.Val316Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.12

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14718291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6 linkuse as main transcript	c.946G>A	p.Val316Met	missense_variant	7/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7 linkuse as main transcript	c.946G>A	p.Val316Met	missense_variant	7/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251460

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000118

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000795

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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 07, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Val316Met in SERPINB6 has not been previously reported in individuals with hearing loss, but it has been identified in 0.04% (10/24028) of African chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs550855004). The valine (Val) at position 316 is not conserved in mammals or evolutionarily distant species, with two mammals having a methionine (Met), supporting that a c hange at this position may be tolerated. Additional computational prediction too ls do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of this variant is uncertain, the conserv ation data suggest that it is more likely to be benign. ACMG/AMP criteria applie d: PS4_Supporting, BP4. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 20, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 316 of the SERPINB6 protein (p.Val316Met). This variant is present in population databases (rs550855004, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 667324). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.25

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

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.17

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.28

Sift

Benign

0.10

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

Sift4G

Benign

0.13

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

Polyphen

0.61

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

Vest4

0.13

MVP

0.77

MPC

0.18

ClinPred

0.013

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.50

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