2-31524923-T-C

Position:

• chr2-31524923-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000348.4(SRD5A2):​c.*1273A>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 0.00962 in 224,642 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (3 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.523

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=-0.81).
• BP6: Variant 2-31524923-T-C is Benign according to our data. Variant chr2-31524923-T-C is described in ClinVar as [Benign]. Clinvar id is 335803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00965 (1469/152302) while in subpopulation SAS AF= 0.0444 (214/4824). AF 95% confidence interval is 0.0395. There are 22 homozygotes in gnomad4. There are 733 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.*1273A>G		3_prime_UTR_variant	5/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.*1273A>G		3_prime_UTR_variant	5/5
SRD5A2	XM_011533072.3	c.*1273A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*1273A>G		3_prime_UTR_variant	5/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1472 AN: 152184 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00958 AC: 693 AN: 72340 Hom.: 3 Cov.: 0 AF XY: 0.00943 AC XY: 314 AN XY: 33312

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.00725

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0492

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.00965 AC: 1469 AN: 152302 Hom.: 22 Cov.: 32 AF XY: 0.00984 AC XY: 733 AN XY: 74472

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00517

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0444

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0117 Hom.: 24

Bravo AF: 0.00714

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.59

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: rs28383086; hg19: chr2-31749993;