rs80359852

Positions:

• chr8-27777059-GA-G
• chr8-27777059-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001017420.3(ESCO2):​c.760del​(p.Thr254LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,598,802 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: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ESCO2 NM_001017420.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.892

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]

ACMG classification

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 8-27777059-GA-G is Pathogenic according to our data. Variant chr8-27777059-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 21247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-27777059-GA-G is described in Lovd as [Pathogenic]. Variant chr8-27777059-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESCO2	NM_001017420.3	c.760del	p.Thr254LeufsTer13	frameshift_variant	3/11	ENST00000305188.13	NP_001017420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESCO2	ENST00000305188.13	c.760del	p.Thr254LeufsTer13	frameshift_variant	3/11	1	NM_001017420.3	ENSP00000306999	P1
ESCO2	ENST00000524293.1	n.778del		non_coding_transcript_exon_variant	2/2	1
ESCO2	ENST00000522378.5	c.760del	p.Thr254LeufsTer13	frameshift_variant, NMD_transcript_variant	3/12	1		ENSP00000428928
ESCO2	ENST00000523910.1	n.559del		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1447440 Hom.: 0 Cov.: 32 AF XY: 0.0000181 AC XY: 13 AN XY: 719550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000954

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151362 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73936

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Thr254Leufs*13) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Roberts syndrome (PMID: 16380922, 18411254). This variant is also known as c.752delA and p.K253fsX12. ClinVar contains an entry for this variant (Variation ID: 21247). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	The c.760delA variant (also known as c.752delA due to alternate nomenclature) in the ESCO2 gene has been reported previously with a second variant in ESCO2 in several unrelated individuals with diagnoses of Roberts-SC phocomelia syndrome (Schule et al., 2005; Gordillo et al., 2008). The c.760delA variant causes a frameshift starting with codon Threonine 254, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr254LeufsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.760delA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.760delA as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -

Roberts-SC phocomelia syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Roberts syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359852; hg19: chr8-27634576;