rs6259

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040.5(SHBG):c.1066G>A(p.Asp356Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,714 control chromosomes in the GnomAD database, including 10,370 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 652 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9718 hom. )

Consequence

SHBG
NM_001040.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0800

Publications

185 publications found

Variant links:

Genes affected

SHBG (HGNC:10839): (sex hormone binding globulin) This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver but is now thought to participate in the regulation of steroid responses. The encoded protein transports androgens and estrogens in the blood, binding each steroid molecule as a dimer formed from identical or nearly identical monomers. Polymorphisms in this gene have been associated with polycystic ovary syndrome and type 2 diabetes mellitus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

SHBG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013456345).

BP6

Variant 17-7633209-G-A is Benign according to our data. Variant chr17-7633209-G-A is described in ClinVar as Benign. ClinVar VariationId is 1222450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHBG	NM_001040.5 link	c.1066G>A	p.Asp356Asn	missense_variant	Exon 8 of 8	ENST00000380450.9	NP_001031.2	P04278-1B0FWH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHBG	ENST00000380450.9 link	c.1066G>A	p.Asp356Asn	missense_variant	Exon 8 of 8	1	NM_001040.5	ENSP00000369816.4		P04278-1

Frequencies

GnomAD3 genomes

AF:

0.0813

AC:

12373

AN:

152098

Hom.:

651

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0294

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.0698

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.0507

Gnomad FIN

AF:

0.0671

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.0867

GnomAD2 exomes

AF:

0.0891

AC:

22407

AN:

251470

AF XY:

0.0888

show subpopulations

Gnomad AFR exome

AF:

0.0263

Gnomad AMR exome

AF:

0.0583

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.0738

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.0936

GnomAD4 exome

AF:

0.110

AC:

161088

AN:

1461498

Hom.:

9718

Cov.:

AF XY:

0.107

AC XY:

78077

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0255

AC:

852

AN:

33476

American (AMR)

AF:

0.0590

AC:

2638

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3162

AN:

26134

East Asian (EAS)

AF:

0.117

AC:

4655

AN:

39698

South Asian (SAS)

AF:

0.0405

AC:

3489

AN:

86250

European-Finnish (FIN)

AF:

0.0771

AC:

4119

AN:

53408

Middle Eastern (MID)

AF:

0.0536

AC:

309

AN:

5768

European-Non Finnish (NFE)

AF:

0.122

AC:

135465

AN:

1111648

Other (OTH)

AF:

0.106

AC:

6399

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

7742

15485

23227

30970

38712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4948

9896

14844

19792

24740

<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:

0.0813

AC:

12368

AN:

152216

Hom.:

652

Cov.:

AF XY:

0.0782

AC XY:

5816

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0294

AC:

1221

AN:

41538

American (AMR)

AF:

0.0697

AC:

1065

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

414

AN:

3470

East Asian (EAS)

AF:

0.115

AC:

595

AN:

5176

South Asian (SAS)

AF:

0.0501

AC:

242

AN:

4826

European-Finnish (FIN)

AF:

0.0671

AC:

711

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7834

AN:

68002

Other (OTH)

AF:

0.0858

AC:

181

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

558

1116

1674

2232

2790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.102

Hom.:

2948

Bravo

AF:

0.0837

TwinsUK

AF:

0.122

AC:

453

ALSPAC

AF:

0.126

AC:

485

ESP6500AA

AF:

0.0359

AC:

158

ESP6500EA

AF:

0.121

AC:

1044

ExAC

AF:

0.0899

AC:

10918

Asia WGS

AF:

0.0670

AC:

231

AN:

3478

EpiCase

AF:

0.114

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 23, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10424400, 19649728, 20974254, 23305451, 19168589, 17315164, 19679209, 21454829) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SHBG-related disorder

Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0064

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.70

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

MetaRNN

Benign

0.0013

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

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

PhyloP100

0.080

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.16

Sift

Benign

0.088

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

Sift4G

Benign

0.62

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

Polyphen

0.0060, 0.0010

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

Vest4

0.056

MPC

0.11

ClinPred

0.0037

GERP RS

-0.55

Varity_R

0.043

gMVP

0.13

Mutation Taster

=97/3

polymorphism (auto)

(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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over