chr2-31531371-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong

The NM_000348.4(SRD5A2):c.547G>A(p.Gly183Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,575,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 missense, splice_region

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.50

Publications

16 publications found

Variant links:

Genes affected

SRD5A2 (HGNC:11285): (steroid 5 alpha-reductase 2) This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH). [provided by RefSeq, Jul 2008]

SRD5A2 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

SRD5A2 links:

ENSG00000228563 (HGNC:):

ENSG00000228563 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -0.88748 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-31531371-C-T is Pathogenic according to our data. Variant chr2-31531371-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.547G>A	p.Gly183Ser	missense splice_region	Exon 3 of 5	NP_000339.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.547G>A	p.Gly183Ser	missense splice_region	Exon 3 of 5	ENSP00000477587.1	P31213
SRD5A2	ENST00000882642.1		c.649G>A	p.Gly217Ser	missense splice_region	Exon 4 of 6	ENSP00000552701.1
SRD5A2	ENST00000882643.1		c.446-1914G>A		intron	N/A	ENSP00000552702.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000310

AC:

AN:

193796

AF XY:

0.0000388

show subpopulations

Gnomad AFR exome

AF:

0.000436

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000197

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1422982

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

704272

show subpopulations

African (AFR)

AF:

0.000456

AC:

AN:

32890

American (AMR)

AF:

0.0000256

AC:

AN:

39008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25400

East Asian (EAS)

AF:

0.00

AC:

AN:

38232

South Asian (SAS)

AF:

0.00

AC:

AN:

81008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090776

Other (OTH)

AF:

0.0000678

AC:

AN:

59022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000145

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000636

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000260

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (5)

not provided (1)

SRD5A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Benign

0.96

FATHMM_MKL

Pathogenic

0.97

MetaRNN

Pathogenic

0.80

PhyloP100

7.5

PrimateAI

Uncertain

0.56

Sift4G

Pathogenic

0.0

Vest4

0.94

MVP

0.56

GERP RS

5.5

gMVP

0.89

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 0

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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