2-31580636-G-T

Variant names:

Variant summary

Our verdict is . The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.123

Publications

250 publications found

Variant links:

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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

SRD5A2 links:

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new If you want to explore the variant's impact on the transcript NM_000348.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

Sel.	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

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	P31213
SRD5A2	ENST00000882642.1		c.265C>A	p.Leu89Ile	missense	Exon 1 of 6	ENSP00000552701.1
SRD5A2	ENST00000882643.1		c.265C>A	p.Leu89Ile	missense	Exon 1 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000493

AC:

AN:

202928

AF XY:

0.00000904

show subpopulations

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:

AN:

1424244

Hom.:

Cov.:

AF XY:

0.00000425

AC XY:

AN XY:

706256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32928

American (AMR)

AF:

0.00

AC:

AN:

41202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25448

East Asian (EAS)

AF:

0.00

AC:

AN:

38856

South Asian (SAS)

AF:

0.00

AC:

AN:

83180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1099938

Other (OTH)

AF:

0.00

AC:

AN:

59326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.2

(source)

DANN

Benign

0.71

FATHMM_MKL

Benign

0.096

MetaRNN

Benign

0.11

PhyloP100

0.12

PrimateAI

Benign

0.36

Sift4G

Benign

0.56

PromoterAI

-0.014

Neutral

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over