2-31580682-GA-G

Variant names:

• chr2-31580682-GA-G
• rs1553329427
• NM_000348.4:c.218delT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000348.4(SRD5A2):​c.218delT​(p.Leu73ProfsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 35)
• Consequence: SRD5A2 NM_000348.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.730
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-31580682-GA-G is Pathogenic according to our data. Variant chr2-31580682-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 548143.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.218delT	p.Leu73ProfsTer58	frameshift	Exon 1 of 5	NP_000339.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.218delT	p.Leu73ProfsTer58	frameshift	Exon 1 of 5	ENSP00000477587.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 01, 2018

Institute of Reproductive and Stem Cell Engineering, Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The single-base deletion led to a frameshift mutation which was predicted to result in the formation of a truncated SRD5A2 protein with a stop codon at position 88. Although no functional studies have been performed, a mutant protein lacking several key regions could be pathogenic, be degraded, or confer a loss of function. This variant was detected in compound heterozygosity with NM_000348.3:c.680G>A in twin patients who presented with the same phenotype (perineal hypospadias, micropenis, and bilateral cryptorchidism) and were raised as females.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.73

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: rs1553329427; hg19: chr2-31805752;