rs797045566
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001017420.3(ESCO2):c.911dup(p.Asn304LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
ESCO2
NM_001017420.3 frameshift
NM_001017420.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.02
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 8-27780218-T-TA is Pathogenic according to our data. Variant chr8-27780218-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 210962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ESCO2 | NM_001017420.3 | c.911dup | p.Asn304LysfsTer2 | frameshift_variant | 4/11 | ENST00000305188.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ESCO2 | ENST00000305188.13 | c.911dup | p.Asn304LysfsTer2 | frameshift_variant | 4/11 | 1 | NM_001017420.3 | P1 | |
ESCO2 | ENST00000522378.5 | c.861+3054dup | intron_variant, NMD_transcript_variant | 1 | |||||
ESCO2 | ENST00000518262.5 | c.25dup | p.Asn9LysfsTer2 | frameshift_variant | 1/6 | 3 | |||
ESCO2 | ENST00000523910.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250536Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135392
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460204Hom.: 0 Cov.: 29 AF XY: 0.00000964 AC XY: 7AN XY: 726434
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Roberts-SC phocomelia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 21, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2023 | This sequence change creates a premature translational stop signal (p.Asn304Lysfs*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 (rs797045566, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ESCO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 210962). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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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