2-31580885-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000348.4(SRD5A2):c.16C>T(p.Gln6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,606,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000348.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000169 AC: 4AN: 236872Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130372
GnomAD4 exome AF: 0.00000825 AC: 12AN: 1454252Hom.: 0 Cov.: 37 AF XY: 0.00000553 AC XY: 4AN XY: 722798
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152336Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 74474
ClinVar
Submissions by phenotype
3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Pathogenic:5
This sequence change creates a premature translational stop signal (p.Gln6*) in the SRD5A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SRD5A2 are known to be pathogenic (PMID: 1406794, 1944596). This variant is present in population databases (rs9332960, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with steroid 5-alpha-reductase deficiency (PMID: 12576851, 18314109, 20190539, 21540559). ClinVar contains an entry for this variant (Variation ID: 436859). For these reasons, this variant has been classified as Pathogenic. -
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PM2_Supporting+PVS1+PM3_VeryStrong+PP1+PP4 -
SRD5A2-related disorder Pathogenic:1
The SRD5A2 c.16C>T variant is predicted to result in premature protein termination (p.Gln6*). This variant has been reported in many individuals with 46,XY disorder of sex development due to 5α-reductase type 2 deficiency (Nie M et al. 2011. PubMed ID: 20736251; Cheng. 2019. PubMed ID: 31031332 ). This variant is reported in 0.017% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-31805954-G-A). Nonsense variants in SRD5A2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
The Q6X nonsense variant in the SRD5A2 gene has been reported previously in both the compound heterozgyous and homozgyous state in association with 5-Alpha Reductase Deficiency type 2 (Sasaki et al., 2003; Wang et al., 2004; Sahakitrunguang et al., 2008; Nie et al., 2011; Zhu et al., 2014). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the Q6X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at