Genetic Variant ERCC8:p.Ser390Ser (chr5-60874636-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_000082.4(ERCC8):c.1170C>T(p.Ser390Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,612,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

ERCC8
NM_000082.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.441

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 5-60874636-G-A is Benign according to our data. Variant chr5-60874636-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1080671.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.441 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC8	NM_000082.4 link	c.1170C>T	p.Ser390Ser	synonymous_variant	Exon 12 of 12	ENST00000676185.1	NP_000073.1	Q13216-1
ERCC8	NM_001007233.3 link	c.996C>T	p.Ser332Ser	synonymous_variant	Exon 13 of 13		NP_001007234.1	B3KPW7
ERCC8	NM_001290285.2 link	c.711C>T	p.Ser237Ser	synonymous_variant	Exon 11 of 11		NP_001277214.1	B3KPW7B4DGZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC8	ENST00000676185.1 link	c.1170C>T	p.Ser390Ser	synonymous_variant	Exon 12 of 12		NM_000082.4	ENSP00000501614.1		Q13216-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151582

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248588

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33464

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44702

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26106

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39658

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86010

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53408

Gnomad4 NFE exome

AF:

0.0000639

AC:

AN:

1111808

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60382

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome 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

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151582

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.0000243

AC:

0.000024253

AN:

0.000024253

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000294

AC:

0.0000294334

AN:

0.0000294334

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00

Hom.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

8.0

DANN

Benign

0.70

Mutation Taster

=97/3

polymorphism

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over