Genetic Variant NM_001017420.3:c.862-15dupT (chr8-27780149-G-GT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS1

The NM_001017420.3(ESCO2):c.862-15dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,227,570 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.012 ( 1 hom. )

Consequence

ESCO2
NM_001017420.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.907

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Variant has high frequency in the NFE (0.0125) population. However there is too low homozygotes in high coverage region: (expected more than 32, got 1).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000376 (56/149124) while in subpopulation SAS AF = 0.00341 (16/4694). AF 95% confidence interval is 0.00214. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESCO2	NM_001017420.3 link	c.862-15dupT		intron_variant	Intron 3 of 10	ENST00000305188.13	NP_001017420.1	Q56NI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESCO2	ENST00000305188.13 link	c.862-15dupT		intron_variant	Intron 3 of 10	1	NM_001017420.3	ENSP00000306999.8		Q56NI9-1

Frequencies

GnomAD3 genomes

AF:

0.000376

AC:

AN:

149016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00108

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00341

Gnomad FIN

AF:

0.000100

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.000978

GnomAD2 exomes

AF:

0.00554

AC:

928

AN:

167462

AF XY:

0.00538

show subpopulations

Gnomad AFR exome

AF:

0.00274

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00520

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00455

Gnomad OTH exome

AF:

0.00660

GnomAD4 exome

AF:

0.0116

AC:

12506

AN:

1078446

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

6056

AN XY:

544418

show subpopulations

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

African (AFR)

AF:

0.00824

AC:

205

AN:

24872

American (AMR)

AF:

0.00751

AC:

277

AN:

36862

Ashkenazi Jewish (ASJ)

AF:

0.00866

AC:

177

AN:

20432

East Asian (EAS)

AF:

0.00665

AC:

215

AN:

32340

South Asian (SAS)

AF:

0.0112

AC:

740

AN:

66362

European-Finnish (FIN)

AF:

0.00385

AC:

180

AN:

46728

Middle Eastern (MID)

AF:

0.00658

AC:

AN:

4708

European-Non Finnish (NFE)

AF:

0.0127

AC:

10192

AN:

800796

Other (OTH)

AF:

0.0108

AC:

489

AN:

45346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

Heterozygous variant carriers

1840

3680

5520

7360

9200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000376

AC:

AN:

149124

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

72722

show subpopulations

African (AFR)

AF:

0.000271

AC:

AN:

40652

American (AMR)

AF:

0.00107

AC:

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.000195

AC:

AN:

5126

South Asian (SAS)

AF:

0.00341

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.000100

AC:

AN:

10000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000134

AC:

AN:

67066

Other (OTH)

AF:

0.000968

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0222

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.91

Mutation Taster

=100/0

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

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NM_001017420.3:c.862-15dupT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over