2-31580636-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000348.4(SRD5A2):​c.265C>G​(p.Leu89Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 1,576,058 control chromosomes in the GnomAD database, including 383,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L89L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (38041 hom., cov: 37)
  • Exomes 𝑓: 0.70 (345648 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• 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: Benign. The variant received -19 ACMG points.

• 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=2.2003112E-6).
• BP6: Variant 2-31580636-G-C is Benign according to our data. Variant chr2-31580636-G-C is described in ClinVar as Benign. ClinVar VariationId is 97400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

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>G	p.Leu89Val	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>G	p.Leu89Val	missense	Exon 1 of 5	ENSP00000477587.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 107162 AN: 152146 Hom.: 38009 Cov.: 37

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.756

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.710

GnomAD2 exomes AF: 0.659 AC: 133781 AN: 202928 AF XY: 0.660

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.759

Gnomad EAS exome AF: 0.446

Gnomad FIN exome AF: 0.697

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.695 AC: 989679 AN: 1423794 Hom.: 345648 Cov.: 68 AF XY: 0.692 AC XY: 488786 AN XY: 706000

African (AFR) AF: 0.750 AC: 24707 AN: 32924

American (AMR) AF: 0.625 AC: 25702 AN: 41140

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 19361 AN: 25444

East Asian (EAS) AF: 0.505 AC: 19634 AN: 38842

South Asian (SAS) AF: 0.620 AC: 51557 AN: 83142

European-Finnish (FIN) AF: 0.694 AC: 26471 AN: 38132

Middle Eastern (MID) AF: 0.720 AC: 3746 AN: 5200

European-Non Finnish (NFE) AF: 0.707 AC: 777042 AN: 1099660

Other (OTH) AF: 0.699 AC: 41459 AN: 59310

GnomAD4 genome AF: 0.704 AC: 107245 AN: 152264 Hom.: 38041 Cov.: 37 AF XY: 0.702 AC XY: 52301 AN XY: 74452

African (AFR) AF: 0.745 AC: 30987 AN: 41570

American (AMR) AF: 0.675 AC: 10341 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2624 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2433 AN: 5148

South Asian (SAS) AF: 0.607 AC: 2930 AN: 4826

European-Finnish (FIN) AF: 0.708 AC: 7509 AN: 10610

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48048 AN: 68006

Other (OTH) AF: 0.707 AC: 1495 AN: 2116

Alfa AF: 0.710 Hom.: 6825

Bravo AF: 0.703

TwinsUK AF: 0.707 AC: 2623

ALSPAC AF: 0.702 AC: 2705

ESP6500AA AF: 0.755 AC: 2946

ESP6500EA AF: 0.710 AC: 5907

ExAC AF: 0.637 AC: 75343

Asia WGS AF: 0.508 AC: 1771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

University of Sydney Medical Foundation

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.0
DANN	Benign	0.73
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.0000022	T
PhyloP100		0.12
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.66	T
Vest4		0.14
GERP RS		2.2
PromoterAI		0.00030	Neutral
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV51870732;