rs1554073316

Variant names:

• chr5-60902509-C-T
• rs1554073316
• NM_000082.4:c.551-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000082.4(ERCC8):​c.551-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005202100: Published functional studies demonstrate a damaging effect and show that this variant results in a new 28 amino acid C-terminus and premature termination of the CSA protein (Kleppa et al., 2007)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC8 NM_000082.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.81
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Cockayne syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• UV-sensitive syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• UV-sensitive syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of -37, new splice context is: tttatcttctgatttttcAGata. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005202100: Published functional studies demonstrate a damaging effect and show that this variant results in a new 28 amino acid C-terminus and premature termination of the CSA protein (Kleppa et al., 2007); PMID: 19894250
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-60902509-C-T is Pathogenic according to our data. Variant chr5-60902509-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 558564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000082.4. 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
	ERCC8	NM_000082.4	MANE Select	c.551-1G>A		splice_acceptor intron	N/A	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.377-1G>A		splice_acceptor intron	N/A	NP_001007234.1	B3KPW7
	ERCC8	NM_001290285.2		c.92-1G>A		splice_acceptor intron	N/A	NP_001277214.1	B4DGZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC8	ENST00000676185.1	MANE Select	c.551-1G>A		splice_acceptor intron	N/A	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.551-1G>A		splice_acceptor intron	N/A	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000891473.1		c.562G>A	p.Gly188Ser	missense	Exon 7 of 12	ENSP00000561532.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cockayne syndrome type 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.8
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 36
DS_AL_spliceai		0.77		Position offset: -1

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

Other links and lift over

dbSNP: rs1554073316; hg19: chr5-60198336; COSMIC: COSV99410218; COSMIC: COSV99410218;