NM_000348.4:c.594C>T

Variant names:

• chr2-31529411-G-A
• rs28383064
• NM_000348.4:c.594C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000348.4(SRD5A2):​c.594C>T​(p.Ile198Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,936 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (22 hom.)
• Consequence: SRD5A2 NM_000348.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.463
• Publications: 2 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

ENSG00000228563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-31529411-G-A is Benign according to our data. Variant chr2-31529411-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.463 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 22 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.594C>T	p.Ile198Ile	synonymous	Exon 4 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.594C>T	p.Ile198Ile	synonymous	Exon 4 of 5	ENSP00000477587.1	P31213
	SRD5A2	ENST00000882642.1		c.696C>T	p.Ile232Ile	synonymous	Exon 5 of 6	ENSP00000552701.1
	SRD5A2	ENST00000882643.1		c.492C>T	p.Ile164Ile	synonymous	Exon 3 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00283 AC: 704 AN: 248836 AF XY: 0.00279

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00435

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00344 AC: 5027 AN: 1461590 Hom.: 22 Cov.: 31 AF XY: 0.00333 AC XY: 2418 AN XY: 727066

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00259 AC: 116 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000788 AC: 68 AN: 86246

European-Finnish (FIN) AF: 0.00311 AC: 166 AN: 53402

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.00401 AC: 4463 AN: 1111784

Other (OTH) AF: 0.00280 AC: 169 AN: 60372

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74496

African (AFR) AF: 0.000697 AC: 29 AN: 41584

American (AMR) AF: 0.00484 AC: 74 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00379 AC: 258 AN: 68038

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00368 Hom.: 3

Bravo AF: 0.00306

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.7
DANN	Benign	0.84
PhyloP100		-0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs28383064; hg19: chr2-31754481;