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GeneBe

rs6259

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.081 ( 652 hom., cov: 32)
Exomes 𝑓: 0.11 ( 9718 hom. )

Consequence

SHBG
NM_001040.5 missense

Scores

1
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0800
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons MANE UniProt
SHBGNM_001040.5 linkuse as main transcriptc.1066G>A p.Asp356Asn missense_variant 8/8 ENST00000380450.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SHBGENST00000380450.9 linkuse as main transcriptc.1066G>A p.Asp356Asn missense_variant 8/81 NM_001040.5 P1P04278-1

Frequencies

GnomAD3 genomes
AF:
0.0813
AC:
12373
AN:
152098
Hom.:
651
Cov.:
32
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
GnomAD3 exomes
AF:
0.0891
AC:
22407
AN:
251470
Hom.:
1246
AF XY:
0.0888
AC XY:
12066
AN XY:
135910
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 SAS exome
AF:
0.0411
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.:
33
AF XY:
0.107
AC XY:
78077
AN XY:
727082
show subpopulations
Gnomad4 AFR exome
AF:
0.0255
Gnomad4 AMR exome
AF:
0.0590
Gnomad4 ASJ exome
AF:
0.121
Gnomad4 EAS exome
AF:
0.117
Gnomad4 SAS exome
AF:
0.0405
Gnomad4 FIN exome
AF:
0.0771
Gnomad4 NFE exome
AF:
0.122
Gnomad4 OTH exome
AF:
0.106
GnomAD4 genome
AF:
0.0813
AC:
12368
AN:
152216
Hom.:
652
Cov.:
32
AF XY:
0.0782
AC XY:
5816
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.0294
Gnomad4 AMR
AF:
0.0697
Gnomad4 ASJ
AF:
0.119
Gnomad4 EAS
AF:
0.115
Gnomad4 SAS
AF:
0.0501
Gnomad4 FIN
AF:
0.0671
Gnomad4 NFE
AF:
0.115
Gnomad4 OTH
AF:
0.0858
Alfa
AF:
0.106
Hom.:
2189
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

SHBG-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 04, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 23, 2020This variant is associated with the following publications: (PMID: 10424400, 19649728, 20974254, 23305451, 19168589, 17315164, 19679209, 21454829) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.50
Cadd
Benign
11
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
N
MetaRNN
Benign
0.0013
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI
Benign
0.33
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
T
GERP RS
-0.55
Varity_R
0.043
gMVP
0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6259; hg19: chr17-7536527; COSMIC: COSV61411262; COSMIC: COSV61411262; API