2-31529322-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000348.4(SRD5A2):​c.683C>G​(p.Ala228Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A228T) has been classified as Likely pathogenic.

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

ENSG00000228563 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000348.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-31529323-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -0.88748 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 2-31529322-G-C is Pathogenic according to our data. Variant chr2-31529322-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2573397.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>G	p.Ala228Gly	missense_variant	Exon 4 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.461C>G	p.Ala154Gly	missense_variant	Exon 4 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.428C>G	p.Ala143Gly	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>G	p.Ala228Gly	missense_variant	Exon 4 of 5	1	NM_000348.4	ENSP00000477587.1
ENSG00000228563	ENST00000435713.1	n.255+1622G>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 22, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SRD5A2 c.680C>G (p.Ala227Gly), also known as c.683C>G (p.A228G), results in a non-conservative amino acid change located in the C-terminal domain (IPR001104) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248984 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.680C>G has been reported in the literature in at least one case of SRY-negative 46,XX testicular disorder of sex development, however a second SRD5A2 variant allele was not identified (e.g., Kim_2021). This report does not provide unequivocal conclusions about association of the variant with 3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency. The following publication was ascertained in the context of this evaluation (PMID: 33775494). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Additionally, different missense variants disrupting the same codon, c.680C>T (p.Ala227Val; known in the literature as c.683C>T/p.A228V) and c.679G>A (p.Alla227Thr; known in the literature as c.682G>A/p.A228T), have been classified as pathogenic in ClinVar and reported in the literature in many individuals affected with steroid 5-alpha-reductase deficiency (PMIDs: 32713132, 32784047, 8784107, 20736251, 31031332, 32596280). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Benign	0.92
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Pathogenic	0.85	D
PhyloP100		9.9
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.065	T
Vest4		0.83
GERP RS		5.5
gMVP		0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1553323488; hg19: chr2-31754392;