NM_000500.9:c.293-13C>G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000500.9(CYP21A2):c.293-13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 151,236 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 (★★).
Frequency
Consequence
NM_000500.9 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CYP21A2 | NM_000500.9 | c.293-13C>G | intron_variant | Intron 2 of 9 | ENST00000644719.2 | NP_000491.4 | ||
CYP21A2 | NM_001368143.2 | c.-126C>G | 5_prime_UTR_variant | Exon 3 of 10 | NP_001355072.1 | |||
CYP21A2 | NM_001368144.2 | c.-126C>G | 5_prime_UTR_variant | Exon 2 of 9 | NP_001355073.1 | |||
CYP21A2 | NM_001128590.4 | c.203-13C>G | intron_variant | Intron 1 of 8 | NP_001122062.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00216 AC: 327AN: 151120Hom.: 1 Cov.: 29
GnomAD3 exomes AF: 0.00226 AC: 501AN: 221616Hom.: 0 AF XY: 0.00242 AC XY: 289AN XY: 119232
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00245 AC: 3525AN: 1440550Hom.: 6 Cov.: 74 AF XY: 0.00237 AC XY: 1691AN XY: 714484
GnomAD4 genome AF: 0.00216 AC: 327AN: 151236Hom.: 1 Cov.: 29 AF XY: 0.00207 AC XY: 153AN XY: 73856
ClinVar
Submissions by phenotype
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:24Other:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.220%). 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. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.75). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 24904866, 25630015, 26206692). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
This variant was identified as compound heterozygous with NM_000500.9:c.?_939+50del. -
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The CYP21A2 c.293-13C>G variant is an intronic variant. Across a selection of the available literature, this variant has been reported in a homozygous state in at least 13 individuals with congenital adrenal hyperplasia due to 21-hydroxylase deficiency and in a compound heterozygous state in at least 48 patients (Speiser et al. 1992; Yoo et al. 2013; Hong et al. 2015; Mohamed et al. 2015). In several families, presumably unaffected parents were identified to be heterozygous carriers of the c.293-13C>G variant. This variant is reported at a frequency of 0.003896 in the Ashkenazi Jewish population from the Genome Aggregation Database. Functional studies in COS-7 cells showed absent CYP21A2 activity for this variant (Higashi et al. 1988). Further, the c.293-13C>G variant was shown to result in abnormal splicing, producing a frameshift which results in premature truncation of the protein. Based on the collective evidence, the c.293-13C>G variant is pathogenic for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. -
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This variant present in Intron 2 of the CYP21A2 gene c.293-13A/C>G (NM_000500.7). This variant was observed in a proband with increased level of 17-OHP enzyme (>303.7nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. This variant has a minor allele frequency of 0.1988% and 0.2261% in 1000 genomes and gnomAD Exomes databases respectively. This variant is characterized by the substitution of A or C nucleotide at 13 bp before the end of intron 2 to G, and activates a cryptic upstream 3' splice acceptor site and causing aberrant splicing (New et al., 2013)This variant has been reported for 21-hydroxylase deficiency (Billerbeck AE et al., 2002 PMID: 12213891, Higashi et al., 1988 PMID: 2845408, Speiser et al., 1992 PMID: 1644925). -
Variant interpreted as Pathogenic and reported on 11-12-2018 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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PM3_VeryStrong, PS3 -
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NM_000500.7(CYP21A2):c.293-13C>G is classified as pathogenic in the context of congenital adrenal hyperplasia and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 1644925 and 2845408. Classification of NM_000500.7(CYP21A2):c.293-13C>G is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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Variant summary: CYP21A2 c.293-13C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site, and one predicts the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Higashi_1988). The variant allele was found at a frequency of 0.0023 in 221616 control chromosomes (gnomAD v2.1, Exomes cohort), however, this allele frequency data may be unreliable due to reported possible pseudogene overlap. c.293-13C>G has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Congenital Adrenal Hyperplasia/Salt Wasting, presenting with salt-wasting, simple virilizing, and non-classical phenotypes (e.g., Wilson_2007, New_2013). 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 protein function, finding that COS cells transfected with the variant displayed undetectable steroid 21-hydroxylase activity (e.g., Higashi_1988). Nineteen ClinVar submitters (evaluation after 2014) have cited the variant, with eighteen submitters classifying the variant as pathogenic and only one submitter classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
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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 nonclassic type hyperandrogenism, due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies have shown that this variant causes aberrant splicing which is predicted to cause a frameshift and create a premature termination codon (PMID: 2845408). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (325 heterozygotes, 1 homozygote). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This has been classified as pathogenic by mulitple clinical laboratories in ClinVar and is very well reported in both compound heterozygous and homozygous states in individuals with congenital adrenal hypoplasia (PMIDs: 35355919, 31586465, 32289882). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
PM3_VeryStrong+PS3 -
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This variant is a well-established pathogenic variant and reported as the most frequent nondeletional mutation found in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [PMID: 20301350, 1644925, 2845408, 25041270]. The variant has been reported to cause aberrant splicing of intron 2 resulting in a shift in the translational reading frame [PMID: 20301350, 2845408, 1869518]. -
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not provided Pathogenic:7
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The CYP21A2 c.293-13C>G variant (also known as IVS2-13A/C>G or Intron 2G) has been reported in the published literature to disrupt normal splicing of the CYP21A2 mRNA (PMID: 2845408 (1988)) and is usually associated with classic CAH, either simple virilizing or salt wasting (PMIDs: 1644925 (1992), 12213891 (2002), 12788880 (2003), 12915679 (2003), 18381579 (2008), 31586465 (2020), 32289882 (2020), 32959514 (2020)). The frequency of this variant in the general population, 0.0037 (36/9714 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
This sequence change falls in intron 2 of the CYP21A2 gene. It does not directly change the encoded amino acid sequence of the CYP21A2 protein. 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 variant has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 20080860, 30995443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS2-13A/C>G, I2G, c.293-13A/C>G, In2G. ClinVar contains an entry for this variant (Variation ID: 12155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
PS3, PS4 -
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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, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. In some published literature, this variant is referred to by nucleotide 655 or 656, and also called the intron 2 G, I2G, or I2 splice variant. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 2845408) -
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Inborn genetic diseases Pathogenic:1
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See cases Pathogenic:1
ACMG categories: PS3,PM2,PM3,PP1,PP4,PP5 -
Congenital adrenal hyperplasia Pathogenic:1
This c.293-13C>G variant is among the most frequent pathogenic variants in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency [OMIM 613815.0006]. It causes premature splicing of the intron and a shift in the translational reading frame [PMID 15146390, 25525159]. This variant has been detected in 206 heterozygous and 2 homozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/16-3293310-A-G) and in affected patients at the homozygous state in our internal database. This variant is classified as pathogenic. Homozygosity for this variant is also considered medically actionable. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at