Genetic Variant NM_001017420.3:c.764T>G (chr8-27777072-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017420.3(ESCO2):c.764T>G(p.Phe255Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F255S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ESCO2
NM_001017420.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.333

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16239664).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESCO2	NM_001017420.3	MANE Select	c.764T>G	p.Phe255Cys	missense	Exon 3 of 11	NP_001017420.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESCO2	ENST00000305188.13	TSL:1 MANE Select	c.764T>G	p.Phe255Cys	missense	Exon 3 of 11	ENSP00000306999.8
ESCO2	ENST00000522378.5	TSL:1	n.764T>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000428928.1
ESCO2	ENST00000524293.1	TSL:1	n.782T>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453368

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32744

American (AMR)

AF:

0.00

AC:

AN:

42476

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

83520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110134

Other (OTH)

AF:

0.00

AC:

AN:

59984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

3.1

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.084

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.42

M_CAP

Benign

0.037

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

PhyloP100

-0.33

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.80

REVEL

Benign

0.12

Sift

Benign

0.18

Sift4G

Benign

0.18

Polyphen

0.76

Vest4

0.38

MutPred

0.13

Loss of catalytic residue at F255 (P = 0.0681)

MVP

0.65

MPC

0.18

ClinPred

0.24

GERP RS

0.25

Varity_R

0.056

gMVP

0.23

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over