rs1554554098

chr8-27777058-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001017420.3(ESCO2):c.751dup(p.Glu251GlyfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,454,010 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ESCO2 NM_001017420.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.756

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 12 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 8-27777058-T-TG is Pathogenic according to our data. Variant chr8-27777058-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 1737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESCO2	NM_001017420.3	c.751dup	p.Glu251GlyfsTer30	frameshift_variant	3/11	ENST00000305188.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESCO2	ENST00000305188.13	c.751dup	p.Glu251GlyfsTer30	frameshift_variant	3/11	1	NM_001017420.3	P1
ESCO2	ENST00000524293.1	n.769dup		non_coding_transcript_exon_variant	2/2	1
ESCO2	ENST00000522378.5	c.751dup	p.Glu251GlyfsTer30	frameshift_variant, NMD_transcript_variant	3/12	1
ESCO2	ENST00000523910.1	n.550dup		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1454010 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 722948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Roberts-SC phocomelia syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Glu251Glyfs*30) 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: 15821733). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1737). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1554554098; hg19: chr8-27634575;