2-31529323-C-T

Position:

• chr2-31529323-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000622030.2(SRD5A2):​c.682G>A​(p.Ala228Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A228G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SRD5A2 ENST00000622030.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.84

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]

ENSG00000228563 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in ENST00000622030.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-31529322-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573397.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 2-31529323-C-T is Pathogenic according to our data. Variant chr2-31529323-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.682G>A	p.Ala228Thr	missense_variant	4/5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.460G>A	p.Ala154Thr	missense_variant	4/5		XP_011531371.1
SRD5A2	XM_011533072.3	c.427G>A	p.Ala143Thr	missense_variant	6/7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.682G>A	p.Ala228Thr	missense_variant	4/5	1	NM_000348.4	ENSP00000477587.1
ENSG00000228563	ENST00000435713.1	n.255+1623C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461568 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 16, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Sep 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Sep 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 228 of the SRD5A2 protein (p.Ala228Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 5α-reductase-2 deficiency (PMID: 8723114, 8784107, 9843052, 23633205; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3344). 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) performed at Invitae indicates that this missense variant is expected to disrupt SRD5A2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8789759, 8723114, 23633205, 9843052, 8784107, 30269266) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 22, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Benign	0.94
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Pathogenic	0.92	D
PrimateAI	Uncertain	0.54	T
Sift4G	Uncertain	0.0030	D
Vest4		0.98
MVP		0.53
GERP RS		5.5
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121434249; hg19: chr2-31754393; COSMIC: COSV99252598;