dbSNP rs2236277: SERPINB6:p.Thr18Thr (chr6-2959279-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004568.6(SERPINB6):c.54G>A(p.Thr18Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,613,822 control chromosomes in the GnomAD database, including 83,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7294 hom., cov: 32)

Exomes 𝑓: 0.32 ( 76474 hom. )

Consequence

SERPINB6
NM_004568.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.58

Publications

30 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.015).

BP6

Variant 6-2959279-C-T is Benign according to our data. Variant chr6-2959279-C-T is described in ClinVar as Benign. ClinVar VariationId is 44135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

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.54G>A	p.Thr18Thr	synonymous	Exon 2 of 7	NP_004559.4
SERPINB6	NM_001271823.2		c.111G>A	p.Thr37Thr	synonymous	Exon 2 of 7	NP_001258752.1	A0A087X1N8
SERPINB6	NM_001271822.2		c.96G>A	p.Thr32Thr	synonymous	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.54G>A	p.Thr18Thr	synonymous	Exon 2 of 7	ENSP00000369912.2	P35237
SERPINB6	ENST00000380520.6	TSL:1	c.54G>A	p.Thr18Thr	synonymous	Exon 2 of 7	ENSP00000369891.1	P35237
SERPINB6	ENST00000380524.5	TSL:1	c.54G>A	p.Thr18Thr	synonymous	Exon 2 of 7	ENSP00000369896.1	P35237

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44912

AN:

151954

Hom.:

7291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.500

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.320

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.349

AC:

87707

AN:

251466

AF XY:

0.344

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.495

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.501

Gnomad FIN exome

AF:

0.278

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

AF:

0.319

AC:

466494

AN:

1461752

Hom.:

76474

Cov.:

AF XY:

0.319

AC XY:

232322

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.168

AC:

5626

AN:

33478

American (AMR)

AF:

0.481

AC:

21496

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9790

AN:

26136

East Asian (EAS)

AF:

0.498

AC:

19765

AN:

39700

South Asian (SAS)

AF:

0.334

AC:

28789

AN:

86254

European-Finnish (FIN)

AF:

0.282

AC:

15085

AN:

53404

Middle Eastern (MID)

AF:

0.317

AC:

1828

AN:

5768

European-Non Finnish (NFE)

AF:

0.310

AC:

344659

AN:

1111902

Other (OTH)

AF:

0.322

AC:

19456

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

18207

36414

54621

72828

91035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11384

22768

34152

45536

56920

<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:

0.295

AC:

44914

AN:

152070

Hom.:

7294

Cov.:

AF XY:

0.296

AC XY:

21996

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.182

AC:

7559

AN:

41486

American (AMR)

AF:

0.388

AC:

5937

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

1294

AN:

3470

East Asian (EAS)

AF:

0.500

AC:

2584

AN:

5172

South Asian (SAS)

AF:

0.355

AC:

1712

AN:

4816

European-Finnish (FIN)

AF:

0.277

AC:

2924

AN:

10550

Middle Eastern (MID)

AF:

0.377

AC:

110

AN:

292

European-Non Finnish (NFE)

AF:

0.320

AC:

21753

AN:

67978

Other (OTH)

AF:

0.336

AC:

710

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1590

3180

4770

6360

7950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.323

Hom.:

17977

Bravo

AF:

0.303

Asia WGS

AF:

0.387

AC:

1342

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autosomal recessive nonsyndromic hearing loss 91 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.1

(source)

DANN

Benign

0.62

PhyloP100

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

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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