Genetic Variant SRD5A2:c.*2238A>G (chr2-31523958-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000348.4(SRD5A2):c.*2238A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 217,676 control chromosomes in the GnomAD database, including 2,167 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 0.13 ( 1504 hom., cov: 32)

Exomes 𝑓: 0.13 ( 663 hom. )

Consequence

SRD5A2
NM_000348.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.804

Publications

3 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: Labcorp Genetics (formerly Invitae), Orphanet

SRD5A2 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
SRD5A2	NM_000348.4 link	c.*2238A>G	3_prime_UTR_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3 link	c.*2238A>G	3_prime_UTR_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.*2238A>G	3_prime_UTR_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 link	c.*2238A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20244

AN:

152090

Hom.:

1494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.0877

Gnomad AMR

AF:

0.0953

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0982

Gnomad FIN

AF:

0.0990

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.132

GnomAD4 exome

AF:

0.129

AC:

8467

AN:

65466

Hom.:

663

Cov.:

AF XY:

0.131

AC XY:

3976

AN XY:

30390

show subpopulations

African (AFR)

AF:

0.210

AC:

629

AN:

3000

American (AMR)

AF:

0.0983

AC:

191

AN:

1944

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

1065

AN:

4138

East Asian (EAS)

AF:

0.139

AC:

1322

AN:

9544

South Asian (SAS)

AF:

0.0915

AC:

AN:

568

European-Finnish (FIN)

AF:

0.130

AC:

AN:

Middle Eastern (MID)

AF:

0.193

AC:

AN:

398

European-Non Finnish (NFE)

AF:

0.109

AC:

4400

AN:

40354

Other (OTH)

AF:

0.132

AC:

725

AN:

5474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

368

737

1105

1474

1842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.133

AC:

20287

AN:

152210

Hom.:

1504

Cov.:

AF XY:

0.132

AC XY:

9799

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.201

AC:

8334

AN:

41510

American (AMR)

AF:

0.0953

AC:

1457

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

932

AN:

3472

East Asian (EAS)

AF:

0.105

AC:

541

AN:

5170

South Asian (SAS)

AF:

0.0989

AC:

477

AN:

4822

European-Finnish (FIN)

AF:

0.0990

AC:

1051

AN:

10612

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7081

AN:

68020

Other (OTH)

AF:

0.132

AC:

278

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

888

1777

2665

3554

4442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.117

Hom.:

537

Bravo

AF:

0.138

Asia WGS

AF:

0.106

AC:

367

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.2

(source)

DANN

Benign

0.44

PhyloP100

-0.80

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over