rs1553323488

Variant names:

• chr2-31529322-G-A
• rs1553323488
• NM_000348.4:c.683C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-31529322-G-A
• chr2-31529322-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000348.4(SRD5A2):​c.683C>T​(p.Ala228Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92

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]

ENSG00000228563 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 2-31529322-G-A is Pathogenic according to our data. Variant chr2-31529322-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 459642.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.683C>T	p.Ala228Val	missense_variant	Exon 4 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.461C>T	p.Ala154Val	missense_variant	Exon 4 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.428C>T	p.Ala143Val	missense_variant	Exon 6 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.683C>T	p.Ala228Val	missense_variant	Exon 4 of 5	1	NM_000348.4	ENSP00000477587.1
ENSG00000228563	ENST00000435713.1	n.255+1622G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available"). This sequence change replaces alanine with valine at codon 228 of the SRD5A2 protein (p.Ala228Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with steroid 5 alpha-reductase 2 deficiency (PMID: 20736251, 24665940). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 459642). This variant disrupts the p.Ala228 amino acid residue in SRD5A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8723114, 8784107, 9843052, 23633205, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Benign	0.94
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Pathogenic	0.93	D
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0030	D
Vest4		0.97
MVP		0.71
GERP RS		5.5
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553323488; hg19: chr2-31754392; COSMIC: COSV99252684;