17-7631360-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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 Likely 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

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHBG	NM_001040.5	c.554C>G	p.Pro185Arg	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>G	p.Pro185Arg	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_001040.5	ENSP00000369816.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460290 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T;.;T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.76	T;.;T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	.;.;.;.;M;M;M;M;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.6	.;.;.;D;D;D;D;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	.;.;.;D;D;D;D;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;.;.
Vest4		0.23
MutPred		0.88		.;.;.;.;Gain of methylation at R183 (P = 0.0595);Gain of methylation at R183 (P = 0.0595);Gain of methylation at R183 (P = 0.0595);Gain of methylation at R183 (P = 0.0595);.;
MVP		0.91
MPC		0.22
ClinPred		0.98	D
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7534678;