rs1554952443

Variant names:

• chr11-722116-AC-A
• rs1554952443
• NM_022772.4:c.1014delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022772.4(EPS8L2):​c.1014delC​(p.Ser339AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPS8L2 NM_022772.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.91
• 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: PanelApp Australia, 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 12 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
• PP5: Variant 11-722116-AC-A is Pathogenic according to our data. Variant chr11-722116-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 433529.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022772.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8L2	NM_022772.4	MANE Select	c.1014delC	p.Ser339AlafsTer15	frameshift	Exon 12 of 21	NP_073609.2
	EPS8L2	NM_001441192.1		c.1014delC	p.Ser339AlafsTer15	frameshift	Exon 13 of 22	NP_001428121.1
	EPS8L2	NM_001441193.1		c.1014delC	p.Ser339AlafsTer15	frameshift	Exon 13 of 22	NP_001428122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS8L2	ENST00000318562.13	TSL:1 MANE Select	c.1014delC	p.Ser339AlafsTer15	frameshift	Exon 12 of 21	ENSP00000320828.8
	EPS8L2	ENST00000526198.5	TSL:1	c.1062delC	p.Ser355AlafsTer15	frameshift	Exon 11 of 20	ENSP00000436230.1
	EPS8L2	ENST00000530636.5	TSL:1	c.1014delC	p.Ser339AlafsTer15	frameshift	Exon 12 of 21	ENSP00000436035.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, autosomal recessive 106 Pathogenic:2

Oct 23, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 22, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1554952443; hg19: chr11-722116;