18-36138270-C-CT
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_018255.4(ELP2):c.293dupT(p.Leu98PhefsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
ELP2
NM_018255.4 frameshift
NM_018255.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.84
Genes affected
ELP2 (HGNC:18248): (elongator acetyltransferase complex subunit 2) The protein encoded by this gene is a core subunit of the elongator complex, a histone acetyltransferase complex that associates with RNA polymerase II. In addition to histone acetylation, the encoded protein effects transcriptional elongation and may help remodel chromatin. [provided by RefSeq, May 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-36138270-C-CT is Pathogenic according to our data. Variant chr18-36138270-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1012186.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000335 (51/152250) while in subpopulation AFR AF= 0.00118 (49/41540). AF 95% confidence interval is 0.000916. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ELP2 | NM_018255.4 | c.293dupT | p.Leu98PhefsTer10 | frameshift_variant | Exon 4 of 22 | ENST00000358232.11 | NP_060725.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152132Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251392Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135862
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GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461720Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19AN XY: 727170
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GnomAD4 genome AF: 0.000335 AC: 51AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74438
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal recessive 58 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 24, 2023 | The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 29, 2023 | PVS1, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 10, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2024 | The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge - |
Intellectual disability, profound Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Wainwright Lab, University Of Queensland | - | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at