chr17-7631360-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001040.5(SHBG):c.554C>T(p.Pro185Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,612,554 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0049 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 35 hom. )

Consequence

SHBG
NM_001040.5 missense, splice_region

Scores

Splicing: ADA: 0.1575

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.806

Publications

50 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0106449425).

BP6

Variant 17-7631360-C-T is Benign according to our data. Variant chr17-7631360-C-T is described in ClinVar as Benign. ClinVar VariationId is 3387896.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHBG	NM_001040.5	MANE Select	c.554C>T	p.Pro185Leu	missense splice_region	Exon 4 of 8	NP_001031.2
SHBG	NM_001146279.3		c.554C>T	p.Pro185Leu	missense splice_region	Exon 4 of 8	NP_001139751.1	P04278-5
SHBG	NM_001289113.2		c.380C>T	p.Pro127Leu	missense splice_region	Exon 4 of 8	NP_001276042.1	I3L145

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHBG	ENST00000380450.9	TSL:1 MANE Select	c.554C>T	p.Pro185Leu	missense splice_region	Exon 4 of 8	ENSP00000369816.4	P04278-1
SHBG	ENST00000340624.9	TSL:1	c.380C>T	p.Pro127Leu	missense splice_region	Exon 4 of 8	ENSP00000345675.6	I3L145
SHBG	ENST00000575314.5	TSL:1	c.380C>T	p.Pro127Leu	missense splice_region	Exon 4 of 8	ENSP00000458559.1	I3L145

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00867

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00735

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00449

AC:

1121

AN:

249536

AF XY:

0.00458

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00816

Gnomad NFE exome

AF:

0.00625

Gnomad OTH exome

AF:

0.00526

GnomAD4 exome

AF:

0.00608

AC:

8874

AN:

1460276

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

4351

AN XY:

726366

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33444

American (AMR)

AF:

0.00139

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

285

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000697

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00821

AC:

437

AN:

53250

Middle Eastern (MID)

AF:

0.000384

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.00691

AC:

7686

AN:

1111530

Other (OTH)

AF:

0.00508

AC:

306

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

461

922

1384

1845

2306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.00494

AC:

753

AN:

152278

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41562

American (AMR)

AF:

0.00327

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00867

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00735

AC:

500

AN:

68012

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00603

Hom.:

Bravo

AF:

0.00410

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00452

AC:

549

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00480

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.011

MetaSVM

Uncertain

-0.078

MutationAssessor

Uncertain

2.8

PhyloP100

0.81

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.60

MVP

0.93

MPC

0.17

ClinPred

0.066

GERP RS

2.4

Varity_R

0.52

gMVP

0.40

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.16

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over