Genetic Variant SHBG:p.Pro185Arg (chr17-7631360-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001040.5(SHBG):c.554C>G(p.Pro185Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P185L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SHBG
NM_001040.5 missense, splice_region

Scores

Splicing: ADA: 0.02474

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.806

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

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>G	p.Pro185Arg	missense splice_region	Exon 4 of 8	NP_001031.2
SHBG	NM_001146279.3		c.554C>G	p.Pro185Arg	missense splice_region	Exon 4 of 8	NP_001139751.1	P04278-5
SHBG	NM_001289113.2		c.380C>G	p.Pro127Arg	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>G	p.Pro185Arg	missense splice_region	Exon 4 of 8	ENSP00000369816.4	P04278-1
SHBG	ENST00000340624.9	TSL:1	c.380C>G	p.Pro127Arg	missense splice_region	Exon 4 of 8	ENSP00000345675.6	I3L145
SHBG	ENST00000575314.5	TSL:1	c.380C>G	p.Pro127Arg	missense splice_region	Exon 4 of 8	ENSP00000458559.1	I3L145

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460290

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111540

Other (OTH)

AF:

0.00

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.6

PhyloP100

0.81

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.23

MutPred

0.88

Gain of methylation at R183 (P = 0.0595)

MVP

0.91

MPC

0.22

ClinPred

0.98

GERP RS

2.4

Varity_R

0.48

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.025

dbscSNV1_RF

Benign

0.21

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over