rs1060499834

Positions:

• chr2-31580690-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000348.4(SRD5A2):​c.211C>T​(p.Gln71*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,134 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-31580690-G-A is Pathogenic according to our data. Variant chr2-31580690-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 403724.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.211C>T	p.Gln71*	stop_gained	1/5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533072.3	c.27-46924C>T		intron_variant			XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.211C>T	p.Gln71*	stop_gained	1/5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000863 AC: 2 AN: 231758 Hom.: 0 AF XY: 0.00000786 AC XY: 1 AN XY: 127278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448134 Hom.: 0 Cov.: 37 AF XY: 0.00000139 AC XY: 1 AN XY: 720462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 21, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 403724). This premature translational stop signal has been observed in individuals with steroid-5 alpha-reductase deficiency (PMID: 20736251, 22453073). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln71*) in the SRD5A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SRD5A2 are known to be pathogenic (PMID: 1406794, 1944596). -
Pathogenic, criteria provided, single submitter	clinical testing	Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital	Oct 30, 2015	the genetype:［c.211C>T（p.Gln71*）］＋［c.680G>A（p.Arg227Gln）］ -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	37
DANN	Benign	0.62
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.68
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1060499834; hg19: chr2-31805760;