chr17-7633209-G-C

Variant names:

• chr17-7633209-G-C
• rs6259
• NM_001040.5:c.1066G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040.5(SHBG):​c.1066G>C​(p.Asp356His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. D356N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHBG NM_001040.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 185 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12730178).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHBG	NM_001040.5	MANE Select	c.1066G>C	p.Asp356His	missense	Exon 8 of 8	NP_001031.2
	SHBG	NM_001146279.3		c.1012G>C	p.Asp338His	missense	Exon 8 of 8	NP_001139751.1
	SHBG	NM_001289113.2		c.892G>C	p.Asp298His	missense	Exon 8 of 8	NP_001276042.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHBG	ENST00000380450.9	TSL:1 MANE Select	c.1066G>C	p.Asp356His	missense	Exon 8 of 8	ENSP00000369816.4
	SHBG	ENST00000340624.9	TSL:1	c.892G>C	p.Asp298His	missense	Exon 8 of 8	ENSP00000345675.6
	SHBG	ENST00000575314.5	TSL:1	c.892G>C	p.Asp298His	missense	Exon 8 of 8	ENSP00000458559.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2948

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.080
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.18
Sift	Benign	0.030	D
Sift4G	Benign	0.12	T
Polyphen		0.93	P
Vest4		0.19
MutPred		0.19		Loss of sheet (P = 0.1158)
MVP		0.82
MPC		0.37
ClinPred		0.22	T
GERP RS		-0.55
Varity_R		0.065
gMVP		0.30

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

Other links and lift over

dbSNP: rs6259; hg19: chr17-7536527;