rs141631911

Positions:

• chr8-27777072-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001017420.3(ESCO2):​c.764T>C​(p.Phe255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,605,628 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (71 hom.)
• Consequence: ESCO2 NM_001017420.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.333

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027889013).
• BP6: Variant 8-27777072-T-C is Benign according to our data. Variant chr8-27777072-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 196300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00262 (399/152270) while in subpopulation AMR AF= 0.0182 (279/15300). AF 95% confidence interval is 0.0165. There are 8 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESCO2	NM_001017420.3	c.764T>C	p.Phe255Ser	missense_variant	3/11	ENST00000305188.13	NP_001017420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESCO2	ENST00000305188.13	c.764T>C	p.Phe255Ser	missense_variant	3/11	1	NM_001017420.3	ENSP00000306999.8
ESCO2	ENST00000522378.5	n.764T>C		non_coding_transcript_exon_variant	3/12	1		ENSP00000428928.1
ESCO2	ENST00000524293.1	n.782T>C		non_coding_transcript_exon_variant	2/2	1
ESCO2	ENST00000523910.1	n.563T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 152152 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00803 AC: 1943 AN: 242026 Hom.: 67 AF XY: 0.00627 AC XY: 820 AN XY: 130714

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00683

GnomAD4 exome AF: 0.00192 AC: 2796 AN: 1453358 Hom.: 71 Cov.: 32 AF XY: 0.00169 AC XY: 1224 AN XY: 722530

Gnomad4 AFR exome AF: 0.000641

Gnomad4 AMR exome AF: 0.0477

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00262 AC: 399 AN: 152270 Hom.: 8 Cov.: 33 AF XY: 0.00265 AC XY: 197 AN XY: 74448

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000798 Hom.: 1

Bravo AF: 0.00578

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00664 AC: 806

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2018	- -

Roberts-SC phocomelia syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.9
DANN	Benign	0.82
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.018
Sift	Benign	0.44	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.44
MPC		0.21
ClinPred		0.000031	T
GERP RS		0.25
Varity_R		0.038
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141631911; hg19: chr8-27634589;