rs80359846
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001017420.3(ESCO2):c.307_311del(p.Lys103GlufsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 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
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-27776613-TAAAAG-T is Pathogenic according to our data. Variant chr8-27776613-TAAAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 21243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27776613-TAAAAG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ESCO2 | NM_001017420.3 | c.307_311del | p.Lys103GlufsTer2 | frameshift_variant | 3/11 | ENST00000305188.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ESCO2 | ENST00000305188.13 | c.307_311del | p.Lys103GlufsTer2 | frameshift_variant | 3/11 | 1 | NM_001017420.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461808Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727200
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Roberts syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 28, 2020 | - - |
ESCO2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 14, 2023 | The ESCO2 c.307_311del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys103Glufs*2). This variant was reported in the homozygous state in two affected fetuses (siblings) with Roberts syndrome [reported as c.307_311delAAAGA (p.I102fs*1), family 4 in Schule et al. 2005. PubMed ID: 16380922]. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different small deletion (c.308_309delAA) resulting in a similar protein truncation or frameshift variant (p.K103fs*3) was also reported in an individual with Roberts syndrome (Table 1, Gordillo et al. 2008. PubMed ID: 18411254). Frameshift variants in ESCO2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change creates a premature translational stop signal (p.Lys103Glufs*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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Roberts syndrome (PMID: 16380922, 18411254). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21243). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Roberts-SC phocomelia syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at