rs201126529

Variant names:

• chr5-60903733-G-A
• rs201126529
• NM_000082.4:c.482-17C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000082.4(ERCC8):​c.482-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,610,122 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ERCC8 NM_000082.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-60903733-G-A is Benign according to our data. Variant chr5-60903733-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000395 (60/151918) while in subpopulation EAS AF = 0.00387 (20/5172). AF 95% confidence interval is 0.00256. There are 1 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

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.482-17C>T		intron	N/A	NP_000073.1	Q13216-1
	ERCC8	NM_001007233.3		c.308-17C>T		intron	N/A	NP_001007234.1	B3KPW7
	ERCC8	NM_001290285.2		c.23-17C>T		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.482-17C>T		intron	N/A	ENSP00000501614.1	Q13216-1
	ERCC8	ENST00000265038.10	TSL:1	c.482-17C>T		intron	N/A	ENSP00000265038.6	A0A7I2PE23
	ERCC8	ENST00000497892.6	TSL:1	n.*280-17C>T		intron	N/A	ENSP00000501805.1	A0A6Q8PFI5

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151800 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000551 AC: 138 AN: 250412 AF XY: 0.000539

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000368 AC: 537 AN: 1458204 Hom.: 1 Cov.: 30 AF XY: 0.000360 AC XY: 261 AN XY: 725532

African (AFR) AF: 0.0000599 AC: 2 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00468 AC: 122 AN: 26062

East Asian (EAS) AF: 0.00521 AC: 206 AN: 39550

South Asian (SAS) AF: 0.000279 AC: 24 AN: 85938

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53366

Middle Eastern (MID) AF: 0.000393 AC: 2 AN: 5084

European-Non Finnish (NFE) AF: 0.0000865 AC: 96 AN: 1109984

Other (OTH) AF: 0.000482 AC: 29 AN: 60204

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151918 Hom.: 1 Cov.: 30 AF XY: 0.000539 AC XY: 40 AN XY: 74220

African (AFR) AF: 0.00 AC: 0 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67880

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000502 Hom.: 0

Bravo AF: 0.000268

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.54
DANN	Benign	0.55
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs201126529; hg19: chr5-60199560;