17-7631360-C-T

Variant names:

• chr17-7631360-C-T
• rs6258
• NM_001040.5:c.554C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 -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 id is 3387896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHBG	NM_001040.5	c.554C>T	p.Pro185Leu	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000380450.9	NP_001031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHBG	ENST00000380450.9	c.554C>T	p.Pro185Leu	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_001040.5	ENSP00000369816.4

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152160 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00449 AC: 1121 AN: 249536 Hom.: 6 AF XY: 0.00458 AC XY: 619 AN XY: 135006

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 SAS exome AF: 0.000492

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.: 35 Cov.: 32 AF XY: 0.00599 AC XY: 4351 AN XY: 726366

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000697

Gnomad4 FIN exome AF: 0.00821

Gnomad4 NFE exome AF: 0.00691

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74444

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00620 Hom.: 15

Bravo AF: 0.00410

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00452 AC: 549

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHBG: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T;.;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;D;T;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.8	.;.;.;.;M;M;M;M;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.4	.;.;.;D;D;D;D;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	.;.;.;D;D;D;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;T;D
Polyphen		1.0	D;.;.;.;.;D;.;.;.
Vest4		0.60
MVP		0.93
MPC		0.17
ClinPred		0.066	T
GERP RS		2.4
Varity_R		0.52
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs6258; hg19: chr17-7534678;