rs6161
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000781.3(CYP11A1):c.940G>A(p.Glu314Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,613,102 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000781.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11A1 | NM_000781.3 | c.940G>A | p.Glu314Lys | missense_variant | 5/9 | ENST00000268053.11 | |
CYP11A1 | NM_001099773.2 | c.466G>A | p.Glu156Lys | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11A1 | ENST00000268053.11 | c.940G>A | p.Glu314Lys | missense_variant | 5/9 | 1 | NM_000781.3 | P1 | |
CYP11A1 | ENST00000358632.8 | c.466G>A | p.Glu156Lys | missense_variant | 5/9 | 2 | |||
CYP11A1 | ENST00000566674.5 | c.466G>A | p.Glu156Lys | missense_variant | 5/6 | 5 | |||
CYP11A1 | ENST00000435365.5 | c.940G>A | p.Glu314Lys | missense_variant, NMD_transcript_variant | 5/8 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00248 AC: 378AN: 152184Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00253 AC: 636AN: 251458Hom.: 4 AF XY: 0.00263 AC XY: 358AN XY: 135902
GnomAD4 exome AF: 0.00404 AC: 5906AN: 1460800Hom.: 17 Cov.: 32 AF XY: 0.00398 AC XY: 2895AN XY: 726720
GnomAD4 genome ? AF: 0.00248 AC: 378AN: 152302Hom.: 1 Cov.: 32 AF XY: 0.00234 AC XY: 174AN XY: 74470
ClinVar
Submissions by phenotype
Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency Pathogenic:2Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 10, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 19, 2023 | PS3, PM3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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. - |
Benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 314 of the CYP11A1 protein (p.Glu314Lys). This variant is present in population databases (rs6161, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with primary adrenal insufficiency (PMID: 30299480, 30620006). 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. This variant has only been described in association with primary adrenal insufficiency, when present in trans with another loss of function allele. This variant is not associated with primary adrenal insufficiency when present in the homozygous state. ClinVar contains an entry for this variant (Variation ID: 372354). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2016 | The E314K variant has been reported previously in two unrelated individuals with primary adrenal insufficiency; one individual harbored another CYP11A1 variant in trans whereas the other reported individual had no other molecular findings (Chan et al., 2015). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports E314K was observed in 0.34% (29/8,592) alleles from individuals of European American ancestry. The E314K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The E314K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2023 | Variant summary: CYP11A1 c.940G>A (p.Glu314Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.0025 in 251458 control chromosomes, including 4 homozygotes, and is found predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYP11A1 causing Congenital Adrenal Hyperplasia phenotype (0.00091), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the inability of this data to distinguish the occurrence of this variant in a pseudogene versus the real CYP11A1 gene makes this data unreliable to formulate conclusive opinions. c.940G>A has been reported in the literature in the compound heterozygous state in individuals affected with Adrenal Insufficiency, including multiple cases where it has been reported in trans with a pathogenic variant and in families where it was reported to segregate with the disease phenotype (e.g. Chan_2015, Goursaud_2018, Maharaj_2019, Kolli_2019a), suggesting that the variant is very likely to be associated with disease. To our knowledge, the variant has not been reported in the homozygous state in affected individuals. Several publications report experimental evidence evaluating an impact on protein function (e.g. Goursaud_2018, Maharaj_2019, Kolli_2019a). Minigene assays have indicated that the variant affects mRNA splicing, resulting in the skipping of exon 5, which would result in a frameshift leading to a premature termination codon, and analysis of mRNA from an individual with the variant showed that this occurred in a larger proportion of transcripts than in a control individual, but that not all transcripts were affected. Enzyme activity assays have provided mixed results regarding the variant effect on protein function. Expression of the purified E314K variant protein in Ecoli and expression in COS1 cells showed comparable activity to the WT protein. However, it exhibited reduced protein expression/stability in HEK-293 cells, with approximately 60% activity compared to WT and in V9 cells, enzyme activity was undetectable. The following publications have been ascertained in the context of this evaluation (PMID: 26300845, 30233493, 30299480, 30620006). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1)/likely pathogenic (n=3), benign (n=1)/likely benign (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at