dbSNP rs4647128: ERCC8:c.1042-197A>G (chr5-60887717-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000082.4(ERCC8):c.1042-197A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 152,320 control chromosomes in the GnomAD database, including 62 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 0.024 ( 62 hom., cov: 33)

Consequence

ERCC8
NM_000082.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.149

Publications

10 publications found

Variant links:

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

ERCC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3658/152320) while in subpopulation NFE AF = 0.0374 (2541/68006). AF 95% confidence interval is 0.0362. There are 62 homozygotes in GnomAd4. There are 1720 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4 link	c.1042-197A>G	intron_variant	Intron 10 of 11	ENST00000676185.1	NP_000073.1	Q13216-1
ERCC8	NM_001007233.3 link	c.868-197A>G	intron_variant	Intron 11 of 12		NP_001007234.1	B3KPW7
ERCC8	NM_001290285.2 link	c.583-197A>G	intron_variant	Intron 9 of 10		NP_001277214.1	B3KPW7B4DGZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1 link	c.1042-197A>G		intron_variant	Intron 10 of 11		NM_000082.4	ENSP00000501614.1		Q13216-1

Frequencies

GnomAD3 genomes

AF:

0.0241

AC:

3665

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00588

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0374

Gnomad OTH

AF:

0.0315

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

GnomAD4 genome

AF:

0.0240

AC:

3658

AN:

152320

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1720

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00584

AC:

243

AN:

41588

American (AMR)

AF:

0.0230

AC:

352

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4826

European-Finnish (FIN)

AF:

0.0213

AC:

226

AN:

10616

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0374

AC:

2541

AN:

68006

Other (OTH)

AF:

0.0317

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0348

Hom.:

136

Bravo

AF:

0.0233

Asia WGS

AF:

0.0100

AC:

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over