rs80359847
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001017420.3(ESCO2):c.308_309del(p.Lys103ArgfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,613,924 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
ESCO2
NM_001017420.3 frameshift
NM_001017420.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.82
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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 8-27776613-TAA-T is Pathogenic according to our data. Variant chr8-27776613-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 21244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27776613-TAA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ESCO2 | NM_001017420.3 | c.308_309del | p.Lys103ArgfsTer3 | frameshift_variant | 3/11 | ENST00000305188.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ESCO2 | ENST00000305188.13 | c.308_309del | p.Lys103ArgfsTer3 | frameshift_variant | 3/11 | 1 | NM_001017420.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251124Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135752
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461808Hom.: 0 AF XY: 0.0000151 AC XY: 11AN XY: 727200
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18411254) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21244). This premature translational stop signal has been observed in individual(s) with Roberts syndrome (PMID: 18411254). This variant is present in population databases (rs755226817, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Lys103Argfs*3) 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). - |
Roberts-SC phocomelia syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
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