rs12126088
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_172351.3(CD46):āc.417A>Gā(p.Leu139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,595,512 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0057 ( 3 hom., cov: 33)
Exomes š: 0.0073 ( 48 hom. )
Consequence
CD46
NM_172351.3 synonymous
NM_172351.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.17
Genes affected
CD46 (HGNC:6953): (CD46 molecule) The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. In addition, the encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6, and type IV pili of pathogenic Neisseria. Finally, the protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization. Mutations at this locus have been associated with susceptibility to hemolytic uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 1-207759666-A-G is Benign according to our data. Variant chr1-207759666-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 522216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207759666-A-G is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-2.17 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00574 (875/152346) while in subpopulation NFE AF= 0.00853 (580/68030). AF 95% confidence interval is 0.00795. There are 3 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CD46 | NM_172351.3 | c.417A>G | p.Leu139= | synonymous_variant | 4/13 | ENST00000367042.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CD46 | ENST00000367042.6 | c.417A>G | p.Leu139= | synonymous_variant | 4/13 | 1 | NM_172351.3 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00575 AC: 875AN: 152228Hom.: 3 Cov.: 33
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GnomAD3 exomes AF: 0.00666 AC: 1663AN: 249636Hom.: 9 AF XY: 0.00679 AC XY: 917AN XY: 135082
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GnomAD4 exome AF: 0.00733 AC: 10576AN: 1443166Hom.: 48 Cov.: 26 AF XY: 0.00725 AC XY: 5210AN XY: 719014
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GnomAD4 genome ? AF: 0.00574 AC: 875AN: 152346Hom.: 3 Cov.: 33 AF XY: 0.00576 AC XY: 429AN XY: 74500
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly Benign:3
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Jun 28, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 22, 2015 | - - |
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. - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | CD46: BP4, BP7, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Kidney disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 10, 2020 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at