NM_000348.4:c.446-1013T>C

Variant names:

• chr2-31532485-A-G
• rs7571644
• NM_000348.4:c.446-1013T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000348.4(SRD5A2):​c.446-1013T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 151,884 control chromosomes in the GnomAD database, including 1,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1708 hom., cov: 31)
• Consequence: SRD5A2 NM_000348.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.977
• Publications: 3 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

ENSG00000228563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 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.446-1013T>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.446-1013T>C		intron	N/A	ENSP00000477587.1
	ENSG00000228563	ENST00000435713.1	TSL:3	n.255+4785A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21825 AN: 151764 Hom.: 1697 Cov.: 31

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.144

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.144 AC: 21869 AN: 151884 Hom.: 1708 Cov.: 31 AF XY: 0.143 AC XY: 10595 AN XY: 74256

African (AFR) AF: 0.205 AC: 8470 AN: 41372

American (AMR) AF: 0.102 AC: 1553 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 953 AN: 3468

East Asian (EAS) AF: 0.115 AC: 593 AN: 5154

South Asian (SAS) AF: 0.143 AC: 690 AN: 4812

European-Finnish (FIN) AF: 0.114 AC: 1201 AN: 10564

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.117 AC: 7928 AN: 67954

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.0658 Hom.: 77

Bravo AF: 0.146

Asia WGS AF: 0.133 AC: 461 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.55
PhyloP100		-0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7571644; hg19: chr2-31757555;