8-27776599-GGAGA-G
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001017420.3(ESCO2):c.294_297del(p.Arg99SerfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.000031 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
ESCO2
NM_001017420.3 frameshift
NM_001017420.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.16
Genes affected
ESCO2 (HGNC:27230): (establishment of sister chromatid cohesion N-acetyltransferase 2) This gene encodes a protein that may have acetyltransferase activity and may be required for the establishment of sister chromatid cohesion during the S phase of mitosis. Mutations in this gene have been associated with Roberts syndrome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 8-27776599-GGAGA-G is Pathogenic according to our data. Variant chr8-27776599-GGAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27776599-GGAGA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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ESCO2 | NM_001017420.3 | c.294_297del | p.Arg99SerfsTer2 | frameshift_variant | 3/11 | ENST00000305188.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ESCO2 | ENST00000305188.13 | c.294_297del | p.Arg99SerfsTer2 | frameshift_variant | 3/11 | 1 | NM_001017420.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251054Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135732
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1461822Hom.: 0 AF XY: 0.0000371 AC XY: 27AN XY: 727208
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Roberts-SC phocomelia syndrome Pathogenic:2Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 05, 2014 | The p.Arg99SerfsX2 variant in ESCO2 has been reported in 1 individual with Roberts syndrome (Gordillo 2008), and data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 99 and lead to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss-of-function variants in ESCO2 have been shown to cause Roberts syndrome. In summary, this variant meets our criteria to be classified as pathogenic for Roberts syndrome acting in a recessive manner. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 10, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. This variant was detected in homozygous state. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change creates a premature translational stop signal (p.Arg99Serfs*2) in the ESCO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ESCO2 are known to be pathogenic (PMID: 15821733, 16380922). This variant is present in population databases (rs754138353, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Roberts syndrome (PMID: 18411254). ClinVar contains an entry for this variant (Variation ID: 21242). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 23, 2022 | - - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at