chr8-27780149-G-GTT

Variant names:

• chr8-27780149-G-GTT
• rs375159544
• NM_001017420.3:c.862-16_862-15dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017420.3(ESCO2):​c.862-16_862-15dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,132,536 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Roberts syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESCO2	NM_001017420.3	c.862-16_862-15dupTT		intron_variant	Intron 3 of 10	ENST00000305188.13	NP_001017420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESCO2	ENST00000305188.13	c.862-16_862-15dupTT		intron_variant	Intron 3 of 10	1	NM_001017420.3	ENSP00000306999.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000132 AC: 15 AN: 1132536 Hom.: 0 Cov.: 19 AF XY: 0.0000157 AC XY: 9 AN XY: 572354

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

African (AFR) AF: 0.00 AC: 0 AN: 26236

American (AMR) AF: 0.00 AC: 0 AN: 38896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21758

East Asian (EAS) AF: 0.00 AC: 0 AN: 34408

South Asian (SAS) AF: 0.00 AC: 0 AN: 70778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48768

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4916

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 838978

Other (OTH) AF: 0.0000209 AC: 1 AN: 47798

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91

Splicing

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

Other links and lift over

dbSNP: rs375159544; hg19: chr8-27637666;