rs2281546

Variant names:

• chr2-31531954-T-G
• rs2281546
• NM_000348.4:c.446-482A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000348.4(SRD5A2):​c.446-482A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,044 control chromosomes in the GnomAD database, including 2,302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2302 hom., cov: 32)
• Consequence: SRD5A2 NM_000348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 4 publications found

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

ENSG00000228563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.446-482A>C		intron_variant	Intron 2 of 4	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.224-482A>C		intron_variant	Intron 2 of 4		XP_011531371.1
SRD5A2	XM_011533072.3	c.191-482A>C		intron_variant	Intron 4 of 6		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.446-482A>C		intron_variant	Intron 2 of 4	1	NM_000348.4	ENSP00000477587.1
ENSG00000228563	ENST00000435713.1	n.255+4254T>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24909 AN: 151926 Hom.: 2279 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.159

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.164 AC: 24971 AN: 152044 Hom.: 2302 Cov.: 32 AF XY: 0.161 AC XY: 11991 AN XY: 74310

African (AFR) AF: 0.250 AC: 10356 AN: 41452

American (AMR) AF: 0.114 AC: 1743 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 963 AN: 3468

East Asian (EAS) AF: 0.114 AC: 587 AN: 5166

South Asian (SAS) AF: 0.143 AC: 686 AN: 4806

European-Finnish (FIN) AF: 0.132 AC: 1399 AN: 10576

Middle Eastern (MID) AF: 0.195 AC: 57 AN: 292

European-Non Finnish (NFE) AF: 0.128 AC: 8721 AN: 67978

Other (OTH) AF: 0.159 AC: 336 AN: 2110

Alfa AF: 0.143 Hom.: 2862

Bravo AF: 0.167

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.60
DANN	Benign	0.61
PhyloP100		-0.23

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

Other links and lift over

dbSNP: rs2281546; hg19: chr2-31757024;