NM_001017420.3:c.862-15dupT

Variant names:

• chr8-27780149-G-GT
• rs375159544
• NM_001017420.3:c.862-15dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.907
• Publications: 0 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: 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.

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.862-15dupT		intron	N/A	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.862-25_862-24insT		intron	N/A	ENSP00000306999.8	Q56NI9-1
	ESCO2	ENST00000522378.5	TSL:1	n.861+2980_861+2981insT		intron	N/A	ENSP00000428928.1	E5RFE4
	ESCO2	ENST00000523910.1	TSL:3	n.661-25_661-24insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000376 AC: 56 AN: 149016 Hom.: 0 Cov.: 33

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

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.: 1 Cov.: 19 AF XY: 0.0111 AC XY: 6056 AN XY: 544418

⚠️ 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: 31 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000376 AC: 56 AN: 149124 Hom.: 0 Cov.: 33 AF XY: 0.000523 AC XY: 38 AN XY: 72722

African (AFR) AF: 0.000271 AC: 11 AN: 40652

American (AMR) AF: 0.00107 AC: 16 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5126

South Asian (SAS) AF: 0.00341 AC: 16 AN: 4694

European-Finnish (FIN) AF: 0.000100 AC: 1 AN: 10000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67066

Other (OTH) AF: 0.000968 AC: 2 AN: 2066

Alfa AF: 0.0222 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs375159544; hg19: chr8-27637666; COSMIC: COSV59416063; COSMIC: COSV59416063;