rs9282858

Variant names:

• chr2-31580756-C-T
• rs9282858
• NM_000348.4:c.145G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000348.4(SRD5A2):​c.145G>A​(p.Ala49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,610,538 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A49A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (43 hom., cov: 35)
  • Exomes 𝑓: 0.031 (871 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:5 O:1
• Conservation: PhyloP100: 2.90
• Publications: 114 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: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000348.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -0.88748 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0075003505).
• BP6: Variant 2-31580756-C-T is Benign according to our data. Variant chr2-31580756-C-T is described in ClinVar as Benign. ClinVar VariationId is 3347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3075/152376) while in subpopulation NFE AF = 0.0324 (2202/68032). AF 95% confidence interval is 0.0312. There are 43 homozygotes in GnomAd4. There are 1438 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 5	NP_000339.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 5	ENSP00000477587.1	P31213
	SRD5A2	ENST00000882642.1		c.145G>A	p.Ala49Thr	missense	Exon 1 of 6	ENSP00000552701.1
	SRD5A2	ENST00000882643.1		c.145G>A	p.Ala49Thr	missense	Exon 1 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3075 AN: 152258 Hom.: 43 Cov.: 35

Gnomad AFR AF: 0.00718

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0175 AC: 4187 AN: 238830 AF XY: 0.0176

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00691

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0308 AC: 44852 AN: 1458162 Hom.: 871 Cov.: 38 AF XY: 0.0299 AC XY: 21682 AN XY: 725582

African (AFR) AF: 0.00517 AC: 173 AN: 33460

American (AMR) AF: 0.0132 AC: 589 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00644 AC: 168 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00242 AC: 209 AN: 86210

European-Finnish (FIN) AF: 0.0209 AC: 1056 AN: 50548

Middle Eastern (MID) AF: 0.00210 AC: 12 AN: 5718

European-Non Finnish (NFE) AF: 0.0369 AC: 41038 AN: 1111542

Other (OTH) AF: 0.0267 AC: 1607 AN: 60238

GnomAD4 genome AF: 0.0202 AC: 3075 AN: 152376 Hom.: 43 Cov.: 35 AF XY: 0.0193 AC XY: 1438 AN XY: 74516

African (AFR) AF: 0.00716 AC: 298 AN: 41598

American (AMR) AF: 0.0163 AC: 250 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.0198 AC: 211 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2202 AN: 68032

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0289 Hom.: 189

Bravo AF: 0.0199

ESP6500AA AF: 0.00606 AC: 23

ESP6500EA AF: 0.0306 AC: 251

ExAC AF: 0.0162 AC: 1945

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	2	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (3)
-	-	2	not provided (3)
-	-	1	SRD5A2 POLYMORPHISM (1)
-	1	-	SRD5A2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.80
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0075	T
PhyloP100		2.9
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.0050	D
Vest4		0.82
GERP RS		3.4
PromoterAI		-0.0096	Neutral
gMVP		0.72

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

Other links and lift over

dbSNP: rs9282858; hg19: chr2-31805826;