2-31525347-T-C

Variant names:

• chr2-31525347-T-C
• rs9332975
• NM_000348.4:c.*849A>G

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.*849A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 226,138 control chromosomes in the GnomAD database, including 2,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1502 hom., cov: 32)
  • Exomes 𝑓: 0.13 (746 hom.)
• Consequence: SRD5A2 NM_000348.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.882
• Publications: 15 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=-0.93).
• BP6: Variant 2-31525347-T-C is Benign according to our data. Variant chr2-31525347-T-C is described in ClinVar as Benign. ClinVar VariationId is 97417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.*849A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.*849A>G		3_prime_UTR_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.*849A>G		3_prime_UTR_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.*849A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20246 AN: 152096 Hom.: 1492 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0983

Gnomad FIN AF: 0.0986

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.129 AC: 9557 AN: 73924 Hom.: 746 Cov.: 0 AF XY: 0.130 AC XY: 4438 AN XY: 34108

African (AFR) AF: 0.212 AC: 738 AN: 3480

American (AMR) AF: 0.0929 AC: 208 AN: 2238

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 1207 AN: 4690

East Asian (EAS) AF: 0.139 AC: 1471 AN: 10576

South Asian (SAS) AF: 0.0905 AC: 59 AN: 652

European-Finnish (FIN) AF: 0.148 AC: 8 AN: 54

Middle Eastern (MID) AF: 0.213 AC: 97 AN: 456

European-Non Finnish (NFE) AF: 0.109 AC: 4969 AN: 45588

Other (OTH) AF: 0.129 AC: 800 AN: 6190

GnomAD4 genome AF: 0.133 AC: 20289 AN: 152214 Hom.: 1502 Cov.: 32 AF XY: 0.132 AC XY: 9793 AN XY: 74426

African (AFR) AF: 0.201 AC: 8338 AN: 41522

American (AMR) AF: 0.0945 AC: 1446 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3470

East Asian (EAS) AF: 0.106 AC: 549 AN: 5174

South Asian (SAS) AF: 0.0990 AC: 478 AN: 4830

European-Finnish (FIN) AF: 0.0986 AC: 1046 AN: 10606

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7082 AN: 68000

Other (OTH) AF: 0.132 AC: 279 AN: 2112

Alfa AF: 0.121 Hom.: 3813

Bravo AF: 0.138

Asia WGS AF: 0.105 AC: 366 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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University of Sydney Medical Foundation

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.55
DANN	Benign	0.76
PhyloP100		-0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs9332975; hg19: chr2-31750417;