rs145712014

Variant names:

• chr2-31526227-G-T
• rs145712014
• NM_000348.4:c.734C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_000348.4(SRD5A2):​c.734C>A​(p.Ser245Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,590,454 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.81
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• 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=0.022504747).
• BP6: Variant 2-31526227-G-T is Benign according to our data. Variant chr2-31526227-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436858.

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.734C>A	p.Ser245Tyr	missense	Exon 5 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.734C>A	p.Ser245Tyr	missense	Exon 5 of 5	ENSP00000477587.1	P31213
	SRD5A2	ENST00000882642.1		c.836C>A	p.Ser279Tyr	missense	Exon 6 of 6	ENSP00000552701.1
	SRD5A2	ENST00000882643.1		c.632C>A	p.Ser211Tyr	missense	Exon 4 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000200 AC: 43 AN: 215076 AF XY: 0.000165

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000904 AC: 130 AN: 1438136 Hom.: 0 Cov.: 28 AF XY: 0.0000870 AC XY: 62 AN XY: 712946

African (AFR) AF: 0.00209 AC: 69 AN: 33008

American (AMR) AF: 0.000119 AC: 5 AN: 41928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 39116

South Asian (SAS) AF: 0.000560 AC: 46 AN: 82118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099018

Other (OTH) AF: 0.000151 AC: 9 AN: 59552

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74482

African (AFR) AF: 0.00195 AC: 81 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000225 Hom.: 1

Bravo AF: 0.000714

ESP6500AA AF: 0.00220 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000274 AC: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Benign	0.85
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.023	T
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.57	T
Vest4		0.44
MVP		0.60
GERP RS		4.9
gMVP		0.88

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: rs145712014; hg19: chr2-31751297;