5-60890918-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000082.4(ERCC8):c.1012G>A(p.Asp338Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00073 in 1,613,318 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

ERCC8
NM_000082.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.48

Publications

4 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063987166).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC8	NM_000082.4	MANE Select	c.1012G>A	p.Asp338Asn	missense	Exon 10 of 12	NP_000073.1
ERCC8	NM_001007233.3		c.838G>A	p.Asp280Asn	missense	Exon 11 of 13	NP_001007234.1
ERCC8	NM_001290285.2		c.553G>A	p.Asp185Asn	missense	Exon 9 of 11	NP_001277214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC8	ENST00000676185.1	MANE Select	c.1012G>A	p.Asp338Asn	missense	Exon 10 of 12	ENSP00000501614.1
ERCC8	ENST00000265038.10	TSL:1	c.1069G>A	p.Asp357Asn	missense	Exon 11 of 13	ENSP00000265038.6
ERCC8	ENST00000675042.2		c.838G>A	p.Asp280Asn	missense	Exon 11 of 13	ENSP00000502082.2

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000379

AC:

AN:

250956

AF XY:

0.000413

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000741

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000741

AC:

1083

AN:

1461146

Hom.:

Cov.:

AF XY:

0.000724

AC XY:

526

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33462

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000927

AC:

1030

AN:

1111636

Other (OTH)

AF:

0.000696

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000618

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41444

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000766

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

May 17, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The D338N variant in the ERCC8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not observed in the homozygous state, the D338N variant is observed in 101/126354 (0.080%) alleles from individuals of non-Finnish European background and 113/276718 (0.041%) total alleles in large population cohorts (Lek et al., 2016). The D338N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret D338N as a variant of uncertain significance.

Oct 26, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 338 of the ERCC8 protein (p.Asp338Asn). This variant is present in population databases (rs141845482, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ERCC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 546240). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC8: BS1

Cockayne syndrome type 1

Uncertain:1

Mar 16, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Cockayne syndrome type 1;C3553298:UV-sensitive syndrome 2

Uncertain:1

Mar 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.063

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.011

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.80

PhyloP100

4.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

2.0

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.33

MVP

0.57

MPC

0.051

ClinPred

0.027

GERP RS

5.9

Varity_R

0.51

gMVP

0.54

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over