2-31524840-T-G

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.*1356A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00864 in 226,866 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (9 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.254

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=-0.82).
• BP6: Variant 2-31524840-T-G is Benign according to our data. Variant chr2-31524840-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 97418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00884 (1346/152276) while in subpopulation NFE AF= 0.0113 (768/68018). AF 95% confidence interval is 0.0106. There are 15 homozygotes in gnomad4. There are 650 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.*1356A>C		3_prime_UTR_variant	5/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.*1356A>C		3_prime_UTR_variant	5/5
SRD5A2	XM_011533072.3	c.*1356A>C		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*1356A>C		3_prime_UTR_variant	5/5	1	NM_000348.4	P1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1343 AN: 152158 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00825 AC: 615 AN: 74590 Hom.: 9 Cov.: 0 AF XY: 0.00830 AC XY: 285 AN XY: 34340

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000939

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00970

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152276 Hom.: 15 Cov.: 32 AF XY: 0.00873 AC XY: 650 AN XY: 74466

Gnomad4 AFR AF: 0.00604

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00951 Hom.: 11

Bravo AF: 0.00784

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Likely 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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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	-0.82
Cadd	Benign	0.91
Dann	Benign	0.67

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: rs28383087; hg19: chr2-31749910;