NM_000348.4:c.586G>C

Variant names:

• chr2-31529419-C-G
• rs121434250
• NM_000348.4:c.586G>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.586G>C​(p.Gly196Arg) 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: 7.84

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, 0.917
• PP5: Variant 2-31529419-C-G is Pathogenic according to our data. Variant chr2-31529419-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 548153.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.586G>C	p.Gly196Arg	missense_variant	Exon 4 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.364G>C	p.Gly122Arg	missense_variant	Exon 4 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.331G>C	p.Gly111Arg	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.586G>C	p.Gly196Arg	missense_variant	Exon 4 of 5	1	NM_000348.4	ENSP00000477587.1
ENSG00000228563	ENST00000435713.1	n.255+1719C>G		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 01, 2018

Institute of Reproductive and Stem Cell Engineering, Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The novel mutation p.G196R and a known mutation p.Q6X were identified in a patient who had perineal hypospadias. Although in vitro studies have not been performed to investigate the functional impact of the p.G196R mutation, several lines of evidence suggest that it is a disease-causing mutation. Firstly, codon 196 is highly conserved. Secondly, in silico analysis by the PolyPhen-2 and PROVEAN software predicted p.G196R to be a "probably damaging" and "deleterious" mutation, respectively. Finally, in this same codon, pathogenic mutations G196S and G196D have been identified previously. Experiments have shown that the G196S mutation could reduce the overall enzyme activity and increase the optimum pH slightly. According to the interpretation of the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation p.G196R was likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Benign	0.72
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Pathogenic	0.92	D
PrimateAI	Uncertain	0.71	T
Sift4G	Pathogenic	0.0010	D
Vest4		0.96
MVP		0.63
GERP RS		5.6
gMVP		0.99

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: rs121434250; hg19: chr2-31754489;