rs80359846

Variant names:

• chr8-27776613-TAAAAG-T
• rs80359846
• NM_001017420.3:c.307_311delAAAGA

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.307_311delAAAGA​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• 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]

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 8-27776613-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 rank	MANE	Protein	UniProt
ESCO2	NM_001017420.3	c.307_311delAAAGA	p.Lys103GlufsTer2	frameshift_variant	Exon 3 of 11	ENST00000305188.13	NP_001017420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESCO2	ENST00000305188.13	c.307_311delAAAGA	p.Lys103GlufsTer2	frameshift_variant	Exon 3 of 11	1	NM_001017420.3	ENSP00000306999.8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461808 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Roberts syndrome Pathogenic:1

May 28, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

ESCO2-related disorder Pathogenic:1

Jun 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;C0796099:Juberg-Hayward syndrome Pathogenic:1

May 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Roberts-SC phocomelia syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359846; hg19: chr8-27634130;