rs767564684

chr2-31529385-G-Achr2-31529385-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000348.4(SRD5A2):c.620C>T(p.Ala207Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A207D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000348.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-31529385-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 529238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A2	NM_000348.4	c.620C>T	p.Ala207Val	missense_variant	4/5	ENST00000622030.2
SRD5A2	XM_011533069.3	c.398C>T	p.Ala133Val	missense_variant	4/5
SRD5A2	XM_011533072.3	c.365C>T	p.Ala122Val	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A2	ENST00000622030.2	c.620C>T	p.Ala207Val	missense_variant	4/5	1	NM_000348.4	P1
	ENST00000435713.1	n.255+1685G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Benign	0.73
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Uncertain	0.60	D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.063	T
Vest4		0.55
MVP		0.56
GERP RS		5.7
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-31754455;