rs4732748

chr8-27776547-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017420.3(ESCO2):c.239C>T(p.Ala80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,932 control chromosomes in the GnomAD database, including 9,316 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A80A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (942 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8374 hom.)
• Consequence: ESCO2 NM_001017420.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.0330

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018123686).
• BP6: Variant 8-27776547-C-T is Benign according to our data. Variant chr8-27776547-C-T is described in ClinVar as [Benign]. Clinvar id is 21240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESCO2	NM_001017420.3	c.239C>T	p.Ala80Val	missense_variant	3/11	ENST00000305188.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESCO2	ENST00000305188.13	c.239C>T	p.Ala80Val	missense_variant	3/11	1	NM_001017420.3	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15983 AN: 152088 Hom.: 944 Cov.: 32

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0969

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.115 AC: 28663 AN: 250260 Hom.: 1996 AF XY: 0.118 AC XY: 15955 AN XY: 135340

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.0792

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.244

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0958

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.101 AC: 148296 AN: 1461726 Hom.: 8374 Cov.: 32 AF XY: 0.104 AC XY: 75262 AN XY: 727150

Gnomad4 AFR exome AF: 0.0955

Gnomad4 AMR exome AF: 0.0811

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.214

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0864

Gnomad4 NFE exome AF: 0.0919

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.105 AC: 15972 AN: 152206 Hom.: 942 Cov.: 32 AF XY: 0.105 AC XY: 7814 AN XY: 74432

Gnomad4 AFR AF: 0.0953

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0819

Gnomad4 NFE AF: 0.0969

Gnomad4 OTH AF: 0.124

Alfa AF: 0.104 Hom.: 2218

Bravo AF: 0.105

TwinsUK AF: 0.0917 AC: 340

ALSPAC AF: 0.0898 AC: 346

ESP6500AA AF: 0.0976 AC: 430

ESP6500EA AF: 0.0993 AC: 854

ExAC AF: 0.115 AC: 13903

Asia WGS AF: 0.181 AC: 627 AN: 3476

EpiCase AF: 0.105

EpiControl AF: 0.107

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Roberts-SC phocomelia syndrome Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Juberg-Hayward syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	3.4
Dann	Benign	0.88
DEOGEN2	Benign	0.039	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.025
MPC		0.12
ClinPred		0.00062	T
GERP RS		1.8
Varity_R		0.032
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4732748; hg19: chr8-27634064; COSMIC: COSV59413950; COSMIC: COSV59413950;