NM_001017420.3:c.239C>T

Variant names:

• chr8-27776547-C-T
• rs4732748
• NM_001017420.3:c.239C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:9 O:1
• Conservation: PhyloP100: 0.0330
• Publications: 30 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Roberts syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESCO2	NM_001017420.3	MANE Select	c.239C>T	p.Ala80Val	missense	Exon 3 of 11	NP_001017420.1	Q56NI9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESCO2	ENST00000305188.13	TSL:1 MANE Select	c.239C>T	p.Ala80Val	missense	Exon 3 of 11	ENSP00000306999.8	Q56NI9-1
	ESCO2	ENST00000522378.5	TSL:1	n.239C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000428928.1	E5RFE4
	ESCO2	ENST00000524293.1	TSL:1	n.257C>T		non_coding_transcript_exon	Exon 2 of 2

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

GnomAD2 exomes AF: 0.115 AC: 28663 AN: 250260 AF XY: 0.118

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 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

African (AFR) AF: 0.0955 AC: 3196 AN: 33478

American (AMR) AF: 0.0811 AC: 3628 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4637 AN: 26130

East Asian (EAS) AF: 0.214 AC: 8477 AN: 39680

South Asian (SAS) AF: 0.156 AC: 13435 AN: 86242

European-Finnish (FIN) AF: 0.0864 AC: 4614 AN: 53396

Middle Eastern (MID) AF: 0.161 AC: 928 AN: 5768

European-Non Finnish (NFE) AF: 0.0919 AC: 102174 AN: 1111926

Other (OTH) AF: 0.119 AC: 7207 AN: 60390

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

African (AFR) AF: 0.0953 AC: 3955 AN: 41520

American (AMR) AF: 0.108 AC: 1652 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 603 AN: 3470

East Asian (EAS) AF: 0.239 AC: 1237 AN: 5182

South Asian (SAS) AF: 0.154 AC: 741 AN: 4822

European-Finnish (FIN) AF: 0.0819 AC: 868 AN: 10598

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0969 AC: 6594 AN: 68016

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.104 Hom.: 3048

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Roberts-SC phocomelia syndrome (4)
-	-	2	not provided (2)
-	-	1	Juberg-Hayward syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.033
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.051
Sift	Benign	0.49	T
Sift4G	Benign	0.39	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4732748; hg19: chr8-27634064; COSMIC: COSV59413950; COSMIC: COSV59413950;