2-31525347-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000348.4(SRD5A2):c.*849A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 226,138 control chromosomes in the GnomAD database, including 2,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1502 hom., cov: 32)
  • Exomes 𝑓: 0.13 (746 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.882

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-31525347-T-C is Benign according to our data. Variant chr2-31525347-T-C is described in ClinVar as [Benign]. Clinvar id is 97417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.*849A>G		3_prime_UTR_variant	5/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.*849A>G		3_prime_UTR_variant	5/5
SRD5A2	XM_011533072.3	c.*849A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*849A>G		3_prime_UTR_variant	5/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20246 AN: 152096 Hom.: 1492 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0983

Gnomad FIN AF: 0.0986

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.129 AC: 9557 AN: 73924 Hom.: 746 Cov.: 0 AF XY: 0.130 AC XY: 4438 AN XY: 34108

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.0929

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.0905

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.133 AC: 20289 AN: 152214 Hom.: 1502 Cov.: 32 AF XY: 0.132 AC XY: 9793 AN XY: 74426

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.0945

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.0990

Gnomad4 FIN AF: 0.0986

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.132

Alfa AF: 0.119 Hom.: 2147

Bravo AF: 0.138

Asia WGS AF: 0.105 AC: 366 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Other:1

not provided, no classification provided

literature only

University of Sydney Medical Foundation

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.55
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs9332975; hg19: chr2-31750417;