chr2-31526224-C-T

Position:

chr2-31526224-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000348.4(SRD5A2):c.737G>A(p.Arg246Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,589,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.91

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_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-31526224-C-T is Pathogenic according to our data. Variant chr2-31526224-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3681329). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRD5A2	NM_000348.4 linkuse as main transcript	c.737G>A	p.Arg246Gln	missense_variant	5/5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 linkuse as main transcript	c.515G>A	p.Arg172Gln	missense_variant	5/5		XP_011531371.1
SRD5A2	XM_011533072.3 linkuse as main transcript	c.482G>A	p.Arg161Gln	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.737G>A	p.Arg246Gln	missense_variant	5/5	1	NM_000348.4	ENSP00000477587.1		P31213

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000229

AC:

AN:

214396

Hom.:

AF XY:

0.000296

AC XY:

AN XY:

114920

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000378

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000424

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.000107

AC:

154

AN:

1437714

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

712706

show subpopulations

Gnomad4 AFR exome

AF:

0.0000606

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000307

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000419

Gnomad4 OTH exome

AF:

0.0000840

GnomAD4 genome

AF:

0.000125

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000554

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000275

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000241

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the SRD5A2 protein (p.Arg246Gln). This variant is present in population databases (rs9332967, gnomAD 0.1%). This missense change has been observed in individual(s) with 5-alpha reductase type 2 deficiency (PMID: 1522235, 2665940, 10718838, 14594182, 18097518, 18717241, 19492581, 20190539, 20493473, 20583543, 23329752, 25899528, 26446026, 26980298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459645). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:26446026). A different missense change at the same codon (p.Arg245Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003337). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jul 21, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology	-	- -

SRD5A2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

The SRD5A2 c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with steroid 5-alpha-reductase deficiency (see for example, Table 1, Thigpen et al. 1992. PubMed ID: 1522235; Table 3, Ko et al. 2010. PubMed ID: 20190539; Table 3, Jia et al. 2018. PubMed ID: 29643321). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Arg246Trp) has been reported in multiple individuals with steroid 5-alpha-reductase deficiency (Table 1, Abacı et al. 2018. PubMed ID: 30132287). The c.737G>A (p.Arg246Gln) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Benign

0.88

FATHMM_MKL

Pathogenic

0.99

MetaRNN

Benign

0.37

PrimateAI

Uncertain

0.52

Sift4G

Pathogenic

0.0

Vest4

0.98

MVP

0.61

GERP RS

5.8

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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