rs1404477615

Positions:

• chr5-60918349-TAC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000082.4(ERCC8):​c.313_314delGT​(p.Val105fs) variant causes a frameshift change involving the alteration of a 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: 32)
• Consequence: ERCC8 NM_000082.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.83

Genes affected

ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ERCC8-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 5-60918349-TAC-T is Pathogenic according to our data. Variant chr5-60918349-TAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 558687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60918349-TAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.313_314delGT	p.Val105fs	frameshift_variant	4/12	ENST00000676185.1	NP_000073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.313_314delGT	p.Val105fs	frameshift_variant	4/12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 558687). This sequence change creates a premature translational stop signal (p.Val105Thrfs*6) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 29572252). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 16865293). This variant is also known as T104fsdelTG. -

Cockayne syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1404477615; hg19: chr5-60214176;