5-60890964-G-T

Position:

• chr5-60890964-G-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.966C>A​(p.Tyr322*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000548 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ERCC8 NM_000082.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.33

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]

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 5-60890964-G-T is Pathogenic according to our data. Variant chr5-60890964-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.966C>A	p.Tyr322*	stop_gained	10/12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.792C>A	p.Tyr264*	stop_gained	11/13		NP_001007234.1
ERCC8	NM_001290285.2	c.507C>A	p.Tyr169*	stop_gained	9/11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.966C>A	p.Tyr322*	stop_gained	10/12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461160 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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

Nov 05, 2023

This sequence change creates a premature translational stop signal (p.Tyr322*) 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 individuals with Cockayne syndrome (PMID: 7664335, 19894250, 29572252, 30200888). It is commonly reported in individuals of Israeli Arab Christians ancestry (PMID: 21108394, 29572252). ClinVar contains an entry for this variant (Variation ID: 1715). For these reasons, this variant has been classified as Pathogenic. -

Cockayne syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2010

- -

Cockayne syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 30, 2023

Variant summary: ERCC8 c.966C>A (p.Tyr322X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251116 control chromosomes (gnomAD). c.966C>A has been reported in the literature in multiple individuals affected with Cockayne Syndrome (e.g., Khayat_2010). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 21108394). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.85
GERP RS		4.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434323; hg19: chr5-60186791;