rs145712014

Positions:

chr2-31526227-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The ENST00000622030.2(SRD5A2):c.734C>A(p.Ser245Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,590,454 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SRD5A2
ENST00000622030.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a chain 3-oxo-5-alpha-steroid 4-dehydrogenase 2 (size 253) in uniprot entity S5A2_HUMAN there are 57 pathogenic changes around while only 18 benign (76%) in ENST00000622030.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022504747).

BP6

Variant 2-31526227-G-T is Benign according to our data. Variant chr2-31526227-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436858.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SRD5A2	NM_000348.4 linkuse as main transcript	c.734C>A	p.Ser245Tyr	missense_variant	5/5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3 linkuse as main transcript	c.512C>A	p.Ser171Tyr	missense_variant	5/5		XP_011531371.1
SRD5A2	XM_011533072.3 linkuse as main transcript	c.479C>A	p.Ser160Tyr	missense_variant	7/7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 linkuse as main transcript	c.734C>A	p.Ser245Tyr	missense_variant	5/5	1	NM_000348.4	ENSP00000477587	P1

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000200

AC:

AN:

215076

Hom.:

AF XY:

0.000165

AC XY:

AN XY:

115342

show subpopulations

Gnomad AFR exome

AF:

0.00169

Gnomad AMR exome

AF:

0.000128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000614

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000904

AC:

130

AN:

1438136

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

712946

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.000119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000560

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.10e-7

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.000591

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000949

Hom.:

Bravo

AF:

0.000714

ESP6500AA

AF:

0.00220

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000274

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 14, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2024

Identified in an individual from a 5-alpha-reductase deficiency cohort, however, it is unknown if this was seen in the homozygous state or with a second SRD5A2 variant (PMID: 32380235); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21604088, 32380235, 33469028, 10718838) -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.85

FATHMM_MKL

Uncertain

0.94

MetaRNN

Benign

0.023

PrimateAI

Uncertain

0.55

Sift4G

Benign

0.57

Vest4

0.44

MVP

0.60

GERP RS

4.9

gMVP

0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over