1-119415477-C-G

Variant names:

• chr1-119415477-C-G
• rs139191056
• NM_000198.4:c.58C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000198.4(HSD3B2):​c.58C>G​(p.Arg20Gly) variant causes a missense change involving the alteration of a non-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. R20C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD3B2 NM_000198.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 5 publications found

Genes affected

HSD3B2 (HGNC:5218): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) The protein encoded by this gene is a bifunctional enzyme that catalyzes the oxidative conversion of delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. It plays a crucial role in the biosynthesis of all classes of hormonal steroids. This gene is predominantly expressed in the adrenals and the gonads. Mutations in this gene are associated with 3-beta-hydroxysteroid dehydrogenase, type II, deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2009]

HSD3B2 Gene-Disease associations (from GenCC):

• congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000307032 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000198.4. 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
	HSD3B2	NM_000198.4	MANE Select	c.58C>G	p.Arg20Gly	missense	Exon 2 of 4	NP_000189.1	P26439-1
	HSD3B2	NM_001166120.2		c.58C>G	p.Arg20Gly	missense	Exon 2 of 4	NP_001159592.1	P26439-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD3B2	ENST00000369416.4	TSL:1 MANE Select	c.58C>G	p.Arg20Gly	missense	Exon 2 of 4	ENSP00000358424.3	P26439-1
	HSD3B2	ENST00000543831.5	TSL:3	c.58C>G	p.Arg20Gly	missense	Exon 2 of 4	ENSP00000445122.1	P26439-1
	HSD3B2	ENST00000902254.1		c.58C>G	p.Arg20Gly	missense	Exon 1 of 3	ENSP00000572313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.27
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.045	D
Polyphen		0.71	P
Vest4		0.27
MutPred		0.66		Loss of MoRF binding (P = 0.038)
MVP		0.81
MPC		0.59
ClinPred		0.79	D
GERP RS		0.20
PromoterAI		0.039	Neutral
Varity_R		0.25
gMVP		0.31
Mutation Taster		=82/18	polymorphism

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: rs139191056; hg19: chr1-119958100;