ENST00000318562.13:c.1921_1922insCGCG

Variant names:

• chr11-726470-G-GGCGC
• NM_022772.4:c.1922_1923insGCGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000318562.13(EPS8L2):​c.1922_1923insGCGC​(p.Phe642ArgfsTer130) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPS8L2 ENST00000318562.13 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95
• Publications: 0 publications found

Genes affected

EPS8L2 (HGNC:21296): (EPS8 signaling adaptor L2) This gene encodes a member of the EPS8 gene family. The encoded protein, like other members of the family, is thought to link growth factor stimulation to actin organization, generating functional redundancy in the pathways that regulate actin cytoskeletal remodeling. [provided by RefSeq, Dec 2008]

EPS8L2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 106

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000269915 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000318562.13. 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
	EPS8L2	NM_022772.4	MANE Select	c.1922_1923insGCGC	p.Phe642ArgfsTer130	frameshift	Exon 19 of 21	NP_073609.2
	EPS8L2	NM_001441192.1		c.1922_1923insGCGC	p.Phe642ArgfsTer130	frameshift	Exon 20 of 22	NP_001428121.1
	EPS8L2	NM_001441193.1		c.1922_1923insGCGC	p.Phe642ArgfsTer130	frameshift	Exon 20 of 22	NP_001428122.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8L2	ENST00000318562.13	TSL:1 MANE Select	c.1922_1923insGCGC	p.Phe642ArgfsTer130	frameshift	Exon 19 of 21	ENSP00000320828.8	Q9H6S3-1
	EPS8L2	ENST00000526198.5	TSL:1	c.1970_1971insGCGC	p.Phe658ArgfsTer94	frameshift	Exon 18 of 20	ENSP00000436230.1	Q9H6S3-3
	EPS8L2	ENST00000530636.5	TSL:1	c.1922_1923insGCGC	p.Phe642ArgfsTer99	frameshift	Exon 19 of 21	ENSP00000436035.1	Q9H6S3-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

Other links and lift over

hg19: chr11-726470;