rs6259

Positions:

• chr17-7633209-G-A
• chr17-7633209-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0800

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]

ACMG classification

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	Protein	UniProt
SHBG	NM_001040.5	c.1066G>A	p.Asp356Asn	missense_variant	8/8	ENST00000380450.9	NP_001031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHBG	ENST00000380450.9	c.1066G>A	p.Asp356Asn	missense_variant	8/8	1	NM_001040.5	ENSP00000369816	P1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12373 AN: 152098 Hom.: 651 Cov.: 32

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

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

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

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2020	This variant is associated with the following publications: (PMID: 10424400, 19649728, 20974254, 23305451, 19168589, 17315164, 19679209, 21454829) -

SHBG-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

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	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
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	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.33	T
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	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

Other links and lift over

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