chr2-31580605-A-G

Variant names:

• chr2-31580605-A-G
• rs522638
• NM_000348.4:c.281+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000348.4(SRD5A2):​c.281+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,523,552 control chromosomes in the GnomAD database, including 360,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36117 hom., cov: 37)
  • Exomes 𝑓: 0.69 (324066 hom.)
• Consequence: SRD5A2 NM_000348.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.140
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-31580605-A-G is Benign according to our data. Variant chr2-31580605-A-G is described in ClinVar as Benign. ClinVar VariationId is 97403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 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.281+15T>C		intron	N/A	NP_000339.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.281+15T>C		intron	N/A	ENSP00000477587.1
	SRD5A2	ENST00000882642.1		c.281+15T>C		intron	N/A	ENSP00000552701.1
	SRD5A2	ENST00000882643.1		c.281+15T>C		intron	N/A	ENSP00000552702.1

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104499 AN: 152126 Hom.: 36099 Cov.: 37

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.696

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.646 AC: 97512 AN: 150880 AF XY: 0.647

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.766

Gnomad EAS exome AF: 0.442

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.686 AC: 940620 AN: 1371308 Hom.: 324066 Cov.: 51 AF XY: 0.684 AC XY: 460572 AN XY: 673526

African (AFR) AF: 0.710 AC: 22314 AN: 31434

American (AMR) AF: 0.623 AC: 22041 AN: 35362

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 18061 AN: 23620

East Asian (EAS) AF: 0.512 AC: 18853 AN: 36840

South Asian (SAS) AF: 0.629 AC: 48070 AN: 76430

European-Finnish (FIN) AF: 0.674 AC: 23595 AN: 34982

Middle Eastern (MID) AF: 0.723 AC: 3297 AN: 4562

European-Non Finnish (NFE) AF: 0.696 AC: 745010 AN: 1070954

Other (OTH) AF: 0.689 AC: 39379 AN: 57124

GnomAD4 genome AF: 0.687 AC: 104562 AN: 152244 Hom.: 36117 Cov.: 37 AF XY: 0.686 AC XY: 51054 AN XY: 74444

African (AFR) AF: 0.704 AC: 29261 AN: 41560

American (AMR) AF: 0.669 AC: 10242 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2655 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2448 AN: 5154

South Asian (SAS) AF: 0.617 AC: 2982 AN: 4832

European-Finnish (FIN) AF: 0.689 AC: 7307 AN: 10602

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.696 AC: 47323 AN: 68002

Other (OTH) AF: 0.696 AC: 1469 AN: 2112

Alfa AF: 0.693 Hom.: 55496

Bravo AF: 0.684

Asia WGS AF: 0.515 AC: 1793 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (2)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.6
DANN	Benign	0.23
PhyloP100		0.14
PromoterAI		0.0010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs522638; hg19: chr2-31805675; COSMIC: COSV51872362;