rs145538358

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_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. 17/22 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

Publications

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

SERPINB6 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004568.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 VariationId is 227935.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004568.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINB6	NM_004568.6	MANE Select	c.100A>G	p.Met34Val	missense	Exon 2 of 7	NP_004559.4
SERPINB6	NM_001271823.2		c.157A>G	p.Met53Val	missense	Exon 2 of 7	NP_001258752.1	A0A087X1N8
SERPINB6	NM_001271822.2		c.142A>G	p.Met48Val	missense	Exon 2 of 7	NP_001258751.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINB6	ENST00000380539.7	TSL:3 MANE Select	c.100A>G	p.Met34Val	missense	Exon 2 of 7	ENSP00000369912.2	P35237
SERPINB6	ENST00000380520.6	TSL:1	c.100A>G	p.Met34Val	missense	Exon 2 of 7	ENSP00000369891.1	P35237
SERPINB6	ENST00000380524.5	TSL:1	c.100A>G	p.Met34Val	missense	Exon 2 of 7	ENSP00000369896.1	P35237

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

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251492

AF XY:

0.0000809

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 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

African (AFR)

AF:

0.00269

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.000364

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152306

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000257

Hom.:

Bravo

AF:

0.000744

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.12

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

M_CAP

Benign

0.021

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.68

PhyloP100

2.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.58

REVEL

Benign

0.23

Sift

Benign

0.054

Sift4G

Uncertain

0.047

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.078

gMVP

0.079

Mutation Taster

=93/7

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over