2-31580636-G-T

Variant names:

• chr2-31580636-G-T
• rs523349
• NM_000348.4:c.265C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000348.4(SRD5A2):​c.265C>A​(p.Leu89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign 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. L89V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123
• Publications: 249 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11000469).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.265C>A	p.Leu89Ile	missense	Exon 1 of 5	NP_000339.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.265C>A	p.Leu89Ile	missense	Exon 1 of 5	ENSP00000477587.1

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202928 AF XY: 0.00000904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000211 AC: 3 AN: 1424244 Hom.: 0 Cov.: 68 AF XY: 0.00000425 AC XY: 3 AN XY: 706256

African (AFR) AF: 0.00 AC: 0 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 41202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.00 AC: 0 AN: 38856

South Asian (SAS) AF: 0.00 AC: 0 AN: 83180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5206

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099938

Other (OTH) AF: 0.00 AC: 0 AN: 59326

GnomAD4 genome Cov.: 37

Alfa AF: 0.0000374 Hom.: 6825

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.2
DANN	Benign	0.71
FATHMM_MKL	Benign	0.096	N
MetaRNN	Benign	0.11	T
PhyloP100		0.12
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.56	T
Vest4		0.17
MVP		0.14
GERP RS		2.2
PromoterAI		-0.014	Neutral
gMVP		0.28

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: rs523349; hg19: chr2-31805706;