rs158572

Variant names:

• chr5-60943616-G-A
• rs158572
• NM_000082.4:c.77+1316C>T

Variant summary

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

The NM_000082.4(ERCC8):​c.77+1316C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 151,962 control chromosomes in the GnomAD database, including 31,197 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 0.64 (31197 hom., cov: 32)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0900
• Publications: 17 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.77+1316C>T		intron_variant	Intron 1 of 11	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.-316+1316C>T		intron_variant	Intron 1 of 12		NP_001007234.1
ERCC8	NM_001290285.2	c.-301+1316C>T		intron_variant	Intron 1 of 10		NP_001277214.1
ERCC8	NM_001007234.3	c.77+1316C>T		intron_variant	Intron 1 of 5		NP_001007235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1	c.77+1316C>T		intron_variant	Intron 1 of 11		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96632 AN: 151844 Hom.: 31169 Cov.: 32

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.620

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

GnomAD4 genome AF: 0.636 AC: 96703 AN: 151962 Hom.: 31197 Cov.: 32 AF XY: 0.640 AC XY: 47506 AN XY: 74258

African (AFR) AF: 0.628 AC: 25995 AN: 41418

American (AMR) AF: 0.684 AC: 10453 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1984 AN: 3470

East Asian (EAS) AF: 0.944 AC: 4876 AN: 5166

South Asian (SAS) AF: 0.672 AC: 3237 AN: 4820

European-Finnish (FIN) AF: 0.639 AC: 6736 AN: 10540

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41179 AN: 67950

Other (OTH) AF: 0.624 AC: 1315 AN: 2108

Alfa AF: 0.625 Hom.: 8169

Bravo AF: 0.641

Asia WGS AF: 0.818 AC: 2846 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.4
DANN	Benign	0.19
PhyloP100		-0.090
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs158572; hg19: chr5-60239443;