chr6-32040182-G-GT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000500.9(CYP21A2):c.923dupT(p.Leu308PhefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000500.9 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP21A2 | NM_000500.9 | c.923dupT | p.Leu308PhefsTer6 | frameshift_variant | Exon 7 of 10 | ENST00000644719.2 | NP_000491.4 | |
CYP21A2 | NM_001128590.4 | c.833dupT | p.Leu278PhefsTer6 | frameshift_variant | Exon 6 of 9 | NP_001122062.3 | ||
CYP21A2 | NM_001368143.2 | c.518dupT | p.Leu173PhefsTer6 | frameshift_variant | Exon 7 of 10 | NP_001355072.1 | ||
CYP21A2 | NM_001368144.2 | c.518dupT | p.Leu173PhefsTer6 | frameshift_variant | Exon 6 of 9 | NP_001355073.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000103 AC: 15AN: 1460516Hom.: 0 Cov.: 38 AF XY: 0.00000688 AC XY: 5AN XY: 726586
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74424
ClinVar
Submissions by phenotype
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:6Uncertain:1
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). However, frequency data for this variant in the general population cannot be distinguished from that of the (CYP21P) pseudogene, and are therefore uninformative in assessment of variant pathogenicity. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000065611 / PMID: 1644925). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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The c.923dupT;p.((Leu308Phefs*6) is a null frameshift variant (NMD) in the CYP21A2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65611; PMID: 20301350; PMID: 26206692; PMID: 29035424; PMID: 19169499) - PS4. The p.(Leu308Phefs*6) was detected in trans with a pathogenic variant (PMID: 29035424) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Variant summary: CYP21A2 c.923dupT (p.Leu308PhefsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 246362 control chromosomes. c.923dupT has been reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (de Carvalho_2016, Ezquieta_1995, Friaes_2006, Higashi_1991, Luczay_2006, Speiser_1992), and some of these individuals are reported with other (likely) pathogenic variants in trans. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzymatic activity, finding reduced activity when combined with a missense variant as compared to the missense variant alone or the wildtype construct (Khajuria_2018). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and hyperandrogenism nonclassic type due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 2 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple compound heterozygous patients including as part of complex alleles harbouring multiple variants (ClinVar, LOVD, PMIDs: 35079965, 26804566). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:5
This variant is expected to result in the loss of a functional protein. This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity. (http://gnomad.broadinstitute.org) In multiple individuals with congenital adrenal hyperplasia, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2. -
The c.923dup pathogenic variant (also known as F306+1nt, F306+ T, and L307 frameshift) alters the translation reading frame of the CYP21A2 mRNA and causes the premature termination (p.Leu308Phefs*6) of CYP21A2 protein synthesis. This pathogenic variant is associated with salt-wasting CAH. Based on the available information, this variant is classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Leu308Phefs*6) in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP21A2 are known to be pathogenic (PMID: 10857554). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with classic salt-wasting and simple virilizing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 1644925, 26804566, 28392195, 30995443, 31446012). This variant is also known as F306+T. ClinVar contains an entry for this variant (Variation ID: 65611). For these reasons, this variant has been classified as Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at