Genetic Variant NM_001040.5:c.393+84C>T (chr17-7630953-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001040.5(SHBG):c.393+84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.956 in 1,283,478 control chromosomes in the GnomAD database, including 586,401 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.97 ( 70929 hom., cov: 30)

Exomes 𝑓: 0.95 ( 515472 hom. )

Consequence

SHBG
NM_001040.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.44

Publications

8 publications found

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]

SHBG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SHBG	NM_001040.5	MANE Select	c.393+84C>T	intron	N/A	NP_001031.2
SHBG	NM_001146279.3		c.393+84C>T	intron	N/A	NP_001139751.1	P04278-5
SHBG	NM_001289113.2		c.219+84C>T	intron	N/A	NP_001276042.1	I3L145

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SHBG	ENST00000380450.9	TSL:1 MANE Select	c.393+84C>T	intron	N/A	ENSP00000369816.4	P04278-1
SHBG	ENST00000340624.9	TSL:1	c.219+84C>T	intron	N/A	ENSP00000345675.6	I3L145
SHBG	ENST00000575314.5	TSL:1	c.219+84C>T	intron	N/A	ENSP00000458559.1	I3L145

Frequencies

GnomAD3 genomes

AF:

0.965

AC:

146786

AN:

152086

Hom.:

70868

Cov.:

show subpopulations

Gnomad AFR

AF:

0.991

Gnomad AMI

AF:

0.931

Gnomad AMR

AF:

0.974

Gnomad ASJ

AF:

0.953

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.952

Gnomad FIN

AF:

0.942

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.950

Gnomad OTH

AF:

0.957

GnomAD4 exome

AF:

0.955

AC:

1079840

AN:

1131274

Hom.:

515472

AF XY:

0.954

AC XY:

548656

AN XY:

575056

show subpopulations

African (AFR)

AF:

0.993

AC:

27138

AN:

27316

American (AMR)

AF:

0.981

AC:

40087

AN:

40858

Ashkenazi Jewish (ASJ)

AF:

0.947

AC:

22296

AN:

23538

East Asian (EAS)

AF:

1.00

AC:

37739

AN:

37742

South Asian (SAS)

AF:

0.947

AC:

73294

AN:

77372

European-Finnish (FIN)

AF:

0.939

AC:

41044

AN:

43696

Middle Eastern (MID)

AF:

0.937

AC:

3279

AN:

3498

European-Non Finnish (NFE)

AF:

0.951

AC:

787684

AN:

827882

Other (OTH)

AF:

0.958

AC:

47279

AN:

49372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2616

5233

7849

10466

13082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14260

28520

42780

57040

71300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.965

AC:

146906

AN:

152204

Hom.:

70929

Cov.:

AF XY:

0.966

AC XY:

71860

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.991

AC:

41176

AN:

41530

American (AMR)

AF:

0.974

AC:

14882

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.953

AC:

3308

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5176

AN:

5178

South Asian (SAS)

AF:

0.952

AC:

4588

AN:

4820

European-Finnish (FIN)

AF:

0.942

AC:

9988

AN:

10600

Middle Eastern (MID)

AF:

0.952

AC:

280

AN:

294

European-Non Finnish (NFE)

AF:

0.950

AC:

64642

AN:

68014

Other (OTH)

AF:

0.958

AC:

2019

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

271

542

814

1085

1356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.960

Hom.:

26069

Bravo

AF:

0.969

Asia WGS

AF:

0.983

AC:

3417

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.78

(source)

DANN

Benign

0.91

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over