rs158938

Variant names:

• chr5-60939413-G-A
• rs158938
• NM_000082.4:c.77+5519C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-60939413-G-A
• chr5-60939413-G-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.77+5519C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 151,958 control chromosomes in the GnomAD database, including 33,538 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 0.66 (33538 hom., cov: 31)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.132
• Publications: 6 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4	c.77+5519C>T		intron_variant	Intron 1 of 11	ENST00000676185.1	NP_000073.1
ERCC8	NM_001007233.3	c.-316+5519C>T		intron_variant	Intron 1 of 12		NP_001007234.1
ERCC8	NM_001290285.2	c.-301+5519C>T		intron_variant	Intron 1 of 10		NP_001277214.1
ERCC8	NM_001007234.3	c.77+5519C>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+5519C>T		intron_variant	Intron 1 of 11		NM_000082.4	ENSP00000501614.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100327 AN: 151840 Hom.: 33515 Cov.: 31

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.651

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

GnomAD4 genome AF: 0.661 AC: 100391 AN: 151958 Hom.: 33538 Cov.: 31 AF XY: 0.663 AC XY: 49252 AN XY: 74266

African (AFR) AF: 0.634 AC: 26257 AN: 41426

American (AMR) AF: 0.707 AC: 10799 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2090 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4885 AN: 5180

South Asian (SAS) AF: 0.695 AC: 3345 AN: 4816

European-Finnish (FIN) AF: 0.660 AC: 6964 AN: 10550

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43728 AN: 67936

Other (OTH) AF: 0.655 AC: 1380 AN: 2108

Alfa AF: 0.637 Hom.: 3829

Bravo AF: 0.664

Asia WGS AF: 0.829 AC: 2881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.7
DANN	Benign	0.83
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs158938; hg19: chr5-60235240;