chr2-31526224-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
The NM_000348.4(SRD5A2):c.737G>A(p.Arg246Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,589,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246W) has been classified as Pathogenic.
Frequency
Consequence
NM_000348.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SRD5A2 | NM_000348.4 | c.737G>A | p.Arg246Gln | missense_variant | 5/5 | ENST00000622030.2 | |
SRD5A2 | XM_011533069.3 | c.515G>A | p.Arg172Gln | missense_variant | 5/5 | ||
SRD5A2 | XM_011533072.3 | c.482G>A | p.Arg161Gln | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SRD5A2 | ENST00000622030.2 | c.737G>A | p.Arg246Gln | missense_variant | 5/5 | 1 | NM_000348.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000229 AC: 49AN: 214396Hom.: 0 AF XY: 0.000296 AC XY: 34AN XY: 114920
GnomAD4 exome AF: 0.000107 AC: 154AN: 1437714Hom.: 1 Cov.: 28 AF XY: 0.000133 AC XY: 95AN XY: 712706
GnomAD4 genome AF: 0.000125 AC: 19AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74388
ClinVar
Submissions by phenotype
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000459645). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:26446026). A different missense change at the same codon (p.Arg245Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003337). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 21, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the SRD5A2 protein (p.Arg246Gln). This variant is present in population databases (rs9332967, gnomAD 0.1%). This missense change has been observed in individual(s) with 5-alpha reductase type 2 deficiency (PMID: 1522235, 2665940, 10718838, 14594182, 18097518, 18717241, 19492581, 20190539, 20493473, 20583543, 23329752, 25899528, 26446026, 26980298). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 459645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SRD5A2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 09, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at