Genetic Variant SRD5A2:p.Arg103Arg (chr2-31533741-G-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_000348.4(SRD5A2):c.307C>A(p.Arg103Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000617 in 1,603,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.77

Publications

5 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:

ENSG00000228563 (HGNC:):

ENSG00000228563 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 2-31533741-G-T is Benign according to our data. Variant chr2-31533741-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2709890.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.77 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.307C>A	p.Arg103Arg	synonymous_variant	Exon 2 of 5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 link	c.85C>A	p.Arg29Arg	synonymous_variant	Exon 2 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.52C>A	p.Arg18Arg	synonymous_variant	Exon 4 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 link	c.307C>A	p.Arg103Arg	synonymous_variant	Exon 2 of 5	1	NM_000348.4	ENSP00000477587.1		P31213
ENSG00000228563	ENST00000435713.1 link	n.255+6041G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000957

GnomAD2 exomes

AF:

0.0000946

AC:

AN:

232538

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000954

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000372

AC:

AN:

1451114

Hom.:

Cov.:

AF XY:

0.0000375

AC XY:

AN XY:

720284

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33346

American (AMR)

AF:

0.0000230

AC:

AN:

43486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39338

South Asian (SAS)

AF:

0.00

AC:

AN:

83368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52898

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1106968

Other (OTH)

AF:

0.0000998

AC:

AN:

60104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000295

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000225

Hom.:

Bravo

AF:

0.000389

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.6

(source)

DANN

Benign

0.56

PhyloP100

2.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over