10-49532830-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000124.4(ERCC6):c.135C>G(p.Leu45Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,613,926 control chromosomes in the GnomAD database, including 421,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L45L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.63 ( 32467 hom., cov: 31)

Exomes 𝑓: 0.73 ( 389323 hom. )

Consequence

ERCC6
NM_000124.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.160

Publications

30 publications found

Variant links:

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 Gene-Disease associations (from GenCC):

Cockayne spectrum with or without cerebrooculofacioskeletal syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Cockayne syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
UV-sensitive syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
UV-sensitive syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
premature ovarian failure 11
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ERCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 10-49532830-G-C is Benign according to our data. Variant chr10-49532830-G-C is described in ClinVar as Benign. ClinVar VariationId is 129014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ERCC6	NM_000124.4 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 6	ENST00000447839.7	NP_001263987.1
ERCC6	NM_001346440.2 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 21		NP_001333369.1
ERCC6	NM_001277059.2 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 6		NP_001263988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 21	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000447839.7 link	c.135C>G	p.Leu45Leu	synonymous_variant	Exon 2 of 6	2	NM_001277058.2	ENSP00000387966.2

Frequencies

GnomAD3 genomes

AF:

0.634

AC:

96300

AN:

151930

Hom.:

32459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.692

Gnomad AMR

AF:

0.679

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.813

Gnomad FIN

AF:

0.771

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.741

Gnomad OTH

AF:

0.657

GnomAD2 exomes

AF:

0.698

AC:

175379

AN:

251408

AF XY:

0.715

show subpopulations

Gnomad AFR exome

AF:

0.379

Gnomad AMR exome

AF:

0.635

Gnomad ASJ exome

AF:

0.714

Gnomad EAS exome

AF:

0.528

Gnomad FIN exome

AF:

0.766

Gnomad NFE exome

AF:

0.744

Gnomad OTH exome

AF:

0.729

GnomAD4 exome

AF:

0.726

AC:

1061467

AN:

1461878

Hom.:

389323

Cov.:

115

AF XY:

0.730

AC XY:

531050

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.377

AC:

12632

AN:

33478

American (AMR)

AF:

0.638

AC:

28527

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

18613

AN:

26134

East Asian (EAS)

AF:

0.551

AC:

21857

AN:

39700

South Asian (SAS)

AF:

0.806

AC:

69553

AN:

86258

European-Finnish (FIN)

AF:

0.762

AC:

40708

AN:

53416

Middle Eastern (MID)

AF:

0.724

AC:

4175

AN:

5768

European-Non Finnish (NFE)

AF:

0.740

AC:

822912

AN:

1112006

Other (OTH)

AF:

0.704

AC:

42490

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

22258

44517

66775

89034

111292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20030

40060

60090

80120

100150

<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:

0.634

AC:

96324

AN:

152048

Hom.:

32467

Cov.:

AF XY:

0.641

AC XY:

47654

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.387

AC:

16024

AN:

41428

American (AMR)

AF:

0.679

AC:

10387

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.710

AC:

2465

AN:

3472

East Asian (EAS)

AF:

0.534

AC:

2752

AN:

5158

South Asian (SAS)

AF:

0.813

AC:

3913

AN:

4816

European-Finnish (FIN)

AF:

0.771

AC:

8161

AN:

10590

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.741

AC:

50395

AN:

67978

Other (OTH)

AF:

0.659

AC:

1392

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1589

3178

4766

6355

7944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<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:

0.711

Hom.:

12721

Bravo

AF:

0.611

Asia WGS

AF:

0.656

AC:

2280

AN:

3478

EpiCase

AF:

0.752

EpiControl

AF:

0.751

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2012

Claritas Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

COFS syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebrooculofacioskeletal syndrome 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cockayne syndrome type 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cockayne syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

UV-sensitive syndrome 1

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DE SANCTIS-CACCHIONE SYNDROME

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: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

-0.89

CADD

Benign

0.91

(source)

DANN

Benign

0.31

PhyloP100

-0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over