17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4BP6BS1BS2
The NM_018127.7(ELAC2):c.2415_2416insCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT(p.Arg785_Asp805dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,456,472 control chromosomes in the GnomAD database, including 27 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 27 hom. )
Failed GnomAD Quality Control
Consequence
ELAC2
NM_018127.7 inframe_insertion
NM_018127.7 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.695
Genes affected
ELAC2 (HGNC:14198): (elaC ribonuclease Z 2) The protein encoded by this gene has a C-terminal domain with tRNA 3′ processing endoribonuclease activity, which catalyzes the removal of the 3' trailer from precursor tRNAs. The protein also interacts with activated Smad family member 2 (Smad2) and its nuclear partner forkhead box H1 (also known as FAST-1), and reduced expression can suppress transforming growth factor-beta induced growth arrest. Mutations in this gene result in an increased risk of prostate cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_018127.7.
BP6
Variant 17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG is Benign according to our data. Variant chr17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408865.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00162 (2353/1456472) while in subpopulation NFE AF= 0.00181 (2003/1108126). AF 95% confidence interval is 0.00174. There are 27 homozygotes in gnomad4_exome. There are 1184 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 27 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ELAC2 | NM_018127.7 | c.2415_2416insCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT | p.Arg785_Asp805dup | inframe_insertion | 24/24 | ENST00000338034.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ELAC2 | ENST00000338034.9 | c.2415_2416insCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT | p.Arg785_Asp805dup | inframe_insertion | 24/24 | 1 | NM_018127.7 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 259AN: 152060Hom.: 0 Cov.: 33 FAILED QC
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GnomAD3 exomes AF: 0.000744 AC: 186AN: 249920Hom.: 1 AF XY: 0.000813 AC XY: 110AN XY: 135222
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GnomAD4 exome AF: 0.00162 AC: 2353AN: 1456472Hom.: 27 Cov.: 32 AF XY: 0.00163 AC XY: 1184AN XY: 724764
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00170 AC: 259AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00177 AC XY: 132AN XY: 74388
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2022 | The c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT (p.R785_D805dup) gross duplication spans coding exons XXXX through XXXX in the ELAC2 gene; however, the exact breakpoints of the deletion were not determined. Gene duplications are expected to disrupt gene function; however, it is unclear whether this duplication is disruptive to the ELAC2 gene, or is merely duplicated adjacent to the original xxxx gene or located elsewhere in the genome (Mazzarella, R and Schlessinger, D Genome Res 1998;8:1007-1021). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Combined oxidative phosphorylation defect type 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This variant, c.2353_2415dup, results in the insertion of 21 amino acid(s) of the ELAC2 protein (p.Arg785_Asp805dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
ELAC2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 17, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at