2-31525043-TAAA-TAAAAA

Variant names:

• chr2-31525043-T-TAA
• rs74702388
• NM_000348.4:c.*1151_*1152dupTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000348.4(SRD5A2):​c.*1151_*1152dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 190,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.414
• 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: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0016 (226/141308) while in subpopulation SAS AF = 0.0435 (193/4438). AF 95% confidence interval is 0.0385. There are 2 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.*1151_*1152dupTT		3_prime_UTR	Exon 5 of 5	NP_000339.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.*1151_*1152dupTT		3_prime_UTR	Exon 5 of 5	ENSP00000477587.1	P31213
	SRD5A2	ENST00000882642.1		c.*1151_*1152dupTT		3_prime_UTR	Exon 6 of 6	ENSP00000552701.1
	SRD5A2	ENST00000882643.1		c.*1151_*1152dupTT		3_prime_UTR	Exon 4 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 229 AN: 141262 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000467

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000606

Gnomad SAS AF: 0.0440

Gnomad FIN AF: 0.000234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000934

Gnomad OTH AF: 0.00105

GnomAD4 exome AF: 0.0140 AC: 684 AN: 48966 Hom.: 0 Cov.: 0 AF XY: 0.0132 AC XY: 299 AN XY: 22714

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0157 AC: 34 AN: 2168

American (AMR) AF: 0.0213 AC: 30 AN: 1410

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 36 AN: 3134

East Asian (EAS) AF: 0.0111 AC: 85 AN: 7636

South Asian (SAS) AF: 0.0470 AC: 19 AN: 404

European-Finnish (FIN) AF: 0.0250 AC: 1 AN: 40

Middle Eastern (MID) AF: 0.00645 AC: 2 AN: 310

European-Non Finnish (NFE) AF: 0.0138 AC: 413 AN: 29822

Other (OTH) AF: 0.0158 AC: 64 AN: 4042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00160 AC: 226 AN: 141308 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 163 AN XY: 68484

African (AFR) AF: 0.000466 AC: 18 AN: 38626

American (AMR) AF: 0.000142 AC: 2 AN: 14134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3306

East Asian (EAS) AF: 0.000608 AC: 3 AN: 4936

South Asian (SAS) AF: 0.0435 AC: 193 AN: 4438

European-Finnish (FIN) AF: 0.000234 AC: 2 AN: 8548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000934 AC: 6 AN: 64240

Other (OTH) AF: 0.00104 AC: 2 AN: 1916

Alfa AF: 0.00 Hom.: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74702388; hg19: chr2-31750113;