rs281875224

Variant names:

• chr5-60902454-A-G
• rs281875224
• NM_000082.4:c.605T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000082.4(ERCC8):​c.605T>C​(p.Leu202Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC8 NM_000082.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.05
• 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: Laboratory for Molecular Medicine, Genomics England PanelApp, PanelApp Australia, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000082.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.605T>C	p.Leu202Ser	missense_variant	Exon 7 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.431T>C	p.Leu144Ser	missense_variant	Exon 8 of 13		NP_001007234.1
ERCC8	NM_001290285.2	c.146T>C	p.Leu49Ser	missense_variant	Exon 6 of 11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.605T>C	p.Leu202Ser	missense_variant	Exon 7 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.79		Gain of disorder (P = 0.0138);
MVP		0.94
MPC		0.40
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.85
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs281875224; hg19: chr5-60198281;