2-31525043-TAAA-TAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 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: Benign. The variant received -8 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.
• 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;