rs9332967

Variant names:

• chr2-31526224-C-G
• rs9332967
• NM_000348.4:c.737G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-31526224-C-G
• chr2-31526224-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000348.4(SRD5A2):​c.737G>C​(p.Arg246Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.91
• 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-31526224-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 459645.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, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.737G>C	p.Arg246Pro	missense_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.515G>C	p.Arg172Pro	missense_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.482G>C	p.Arg161Pro	missense_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.737G>C	p.Arg246Pro	missense_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1437714 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 712706

African (AFR) AF: 0.00 AC: 0 AN: 32990

American (AMR) AF: 0.00 AC: 0 AN: 41878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25504

East Asian (EAS) AF: 0.00 AC: 0 AN: 39052

South Asian (SAS) AF: 0.00 AC: 0 AN: 82054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098860

Other (OTH) AF: 0.00 AC: 0 AN: 59528

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Benign	0.88
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.89	D
PhyloP100		6.9
PrimateAI	Uncertain	0.61	T
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MVP		0.61
GERP RS		5.8
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9332967; hg19: chr2-31751294;