Genetic Variant SERPINB6:p.Tyr42Cys (chr6-2959208-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004568.6(SERPINB6):c.125A>G(p.Tyr42Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y42S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SERPINB6
NM_004568.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0560

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 91
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SERPINB6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33125055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB6	NM_004568.6 link	c.125A>G	p.Tyr42Cys	missense_variant	Exon 2 of 7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7 link	c.125A>G	p.Tyr42Cys	missense_variant	Exon 2 of 7	3	NM_004568.6	ENSP00000369912.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.55

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

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.75

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

M_CAP

Benign

0.045

MetaRNN

Benign

0.33

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

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.1

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

PhyloP100

-0.056

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.0090

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

Sift4G

Uncertain

0.036

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

Polyphen

0.84

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

Vest4

0.27

MutPred

0.66

Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);.;.;Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);.;Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);

MVP

0.66

MPC

0.44

ClinPred

0.45

GERP RS

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.22

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over