chr8-142875713-G-T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000497.4(CYP11B1):c.1120C>A(p.Arg374=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,594,996 control chromosomes in the GnomAD database, including 413 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Likely benign.
Frequency
Consequence
NM_000497.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B1 | NM_000497.4 | c.1120C>A | p.Arg374= | splice_region_variant, synonymous_variant | 6/9 | ENST00000292427.10 | |
CYP11B1 | NM_001026213.1 | c.1120C>A | p.Arg374= | splice_region_variant, synonymous_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B1 | ENST00000292427.10 | c.1120C>A | p.Arg374= | splice_region_variant, synonymous_variant | 6/9 | 1 | NM_000497.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0217 AC: 2926AN: 135006Hom.: 24 Cov.: 31
GnomAD3 exomes AF: 0.0174 AC: 4327AN: 248518Hom.: 57 AF XY: 0.0183 AC XY: 2470AN XY: 134656
GnomAD4 exome AF: 0.0220 AC: 32135AN: 1459910Hom.: 389 Cov.: 33 AF XY: 0.0219 AC XY: 15915AN XY: 726290
GnomAD4 genome ? AF: 0.0217 AC: 2929AN: 135086Hom.: 24 Cov.: 31 AF XY: 0.0201 AC XY: 1321AN XY: 65738
ClinVar
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CYP11B1: BP4, BP7, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 24, 2017 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2019 | Variant summary: CYP11B1 c.1120C>A (p.Arg374Arg) 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. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another tool for predicting the outcome of synonymous variants, namely Transcript-inferred Pathogenicity score (TraP, Gelfman_2017) predicts this variant to be possibly pathogenic. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.017 in 248518 control chromosomes in the gnomAD database, including 57 homozygotes. The observed variant frequency is approximately 8.5 fold the estimated maximal allele frequency expected for a pathogenic variant in CYP11B1 causing Congenital Adrenal Hyperplasia phenotype (0.002), strongly suggesting that the variant is benign. c.1120C>A has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia, but without strong evidence for causality (Dundar_2019). This report does not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (too high for associated disease - congenital adrenal hyperplasia) - |
Deficiency of steroid 11-beta-monooxygenase Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Apr 20, 2020 | - - |
Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 05, 2021 | - - |
Glucocorticoid-remediable aldosteronism Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at