8-27777059-GAAAA-GAAAAA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001017420.3(ESCO2):c.760dupA(p.Thr254AsnfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000827 in 1,596,346 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

ESCO2
NM_001017420.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 0.892

Publications

8 publications found

Variant links:

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]

ESCO2 Gene-Disease associations (from GenCC):

Roberts-SC phocomelia syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
Roberts syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ESCO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 8-27777059-G-GA is Pathogenic according to our data. Variant chr8-27777059-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 1738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESCO2	NM_001017420.3 link	c.760dupA	p.Thr254AsnfsTer27	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 link	c.760dupA	p.Thr254AsnfsTer27	frameshift_variant	Exon 3 of 11	1	NM_001017420.3	ENSP00000306999.8

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

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

GnomAD2 exomes

AF:

0.000376

AC:

AN:

225828

AF XY:

0.000392

show subpopulations

Gnomad AFR exome

AF:

0.0000663

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.000243

Gnomad FIN exome

AF:

0.000193

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.000374

GnomAD4 exome

AF:

0.0000893

AC:

129

AN:

1445102

Hom.:

Cov.:

AF XY:

0.0000863

AC XY:

AN XY:

718328

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000185

AC:

AN:

32454

American (AMR)

AF:

0.000789

AC:

AN:

41846

Ashkenazi Jewish (ASJ)

AF:

0.000195

AC:

AN:

25660

East Asian (EAS)

AF:

0.00

AC:

AN:

39448

South Asian (SAS)

AF:

0.000121

AC:

AN:

82886

European-Finnish (FIN)

AF:

0.0000754

AC:

AN:

53028

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000579

AC:

AN:

1104452

Other (OTH)

AF:

0.000101

AC:

AN:

59622

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73808

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41182

American (AMR)

AF:

0.00

AC:

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67798

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000663

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Roberts-SC phocomelia syndrome

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

ESCO2-related disorder

Pathogenic:1

Apr 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ESCO2 c.760dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr254Asnfs*27). This variant was reported to be pathogenic for Roberts Syndrome/SC Phocomelia (see examples: reported as c.751-752insA in Family A, Schule et al. 2005. PubMed ID: 16380922; reported as c.760_761insA, McKay et al. 2018. PubMed ID: 30508616). This variant is reported in 0.084% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in ESCO2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Dec 05, 2023

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.Thr254Asnfs*27) 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 individual(s) with Roberts syndrome (PMID: 18411254, 30508616). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1738). For these reasons, this variant has been classified as Pathogenic. -

Roberts-SC phocomelia syndrome;C0796099:Juberg-Hayward syndrome

Pathogenic:1

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over