NM_000348.4:c.729delC

Variant names:

• chr2-31526231-TG-T
• rs1553323033
• NM_000348.4:c.729delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000348.4(SRD5A2):​c.729delC​(p.Lys244AsnfsTer35) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A2 NM_000348.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.359
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-31526231-TG-T is Pathogenic according to our data. Variant chr2-31526231-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 549757.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.729delC	p.Lys244AsnfsTer35	frameshift_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.507delC	p.Lys170AsnfsTer35	frameshift_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.474delC	p.Lys159AsnfsTer35	frameshift_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.729delC	p.Lys244AsnfsTer35	frameshift_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Jul 23, 2018

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553323033; hg19: chr2-31751301;