rs17332824

Variant names:

• chr5-60870360-C-G
• rs17332824
• NM_000082.4:c.*4255G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000082.4(ERCC8):​c.*4255G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 151,308 control chromosomes in the GnomAD database, including 11,041 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (11041 hom., cov: 29)
• Consequence: ERCC8 NM_000082.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.*4255G>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.*4255G>C		3_prime_UTR_variant	Exon 13 of 13		NP_001007234.1
ERCC8	NM_001290285.2	c.*4255G>C		3_prime_UTR_variant	Exon 11 of 11		NP_001277214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.*4255G>C		3_prime_UTR_variant	Exon 12 of 12		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52029 AN: 151190 Hom.: 11044 Cov.: 29

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.344 AC: 52019 AN: 151308 Hom.: 11041 Cov.: 29 AF XY: 0.348 AC XY: 25696 AN XY: 73912

African (AFR) AF: 0.108 AC: 4458 AN: 41252

American (AMR) AF: 0.399 AC: 6059 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3468

East Asian (EAS) AF: 0.803 AC: 4128 AN: 5140

South Asian (SAS) AF: 0.361 AC: 1722 AN: 4768

European-Finnish (FIN) AF: 0.434 AC: 4517 AN: 10414

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28346 AN: 67794

Other (OTH) AF: 0.366 AC: 764 AN: 2090

Alfa AF: 0.356 Hom.: 1341

Bravo AF: 0.339

Asia WGS AF: 0.555 AC: 1928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.34
PhyloP100		-0.15

Splicing

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

Other links and lift over

dbSNP: rs17332824; hg19: chr5-60166187; COSMIC: COSV54014801;