10-49530735-T-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.528A>G(p.Arg176Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,584 control chromosomes in the GnomAD database, including 660 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. R176R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 59 hom., cov: 32)

Exomes 𝑓: 0.013 ( 601 hom. )

Consequence

ERCC6
NM_000124.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0750

Publications

17 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=-0.53).

BP6

Variant 10-49530735-T-C is Benign according to our data. Variant chr10-49530735-T-C is described in ClinVar as Benign. ClinVar VariationId is 196213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.075 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ERCC6	NM_000124.4 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 6	ENST00000447839.7	NP_001263987.1
ERCC6	NM_001346440.2 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 21		NP_001333369.1
ERCC6	NM_001277059.2 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 6		NP_001263988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 21	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000447839.7 link	c.528A>G	p.Arg176Arg	synonymous_variant	Exon 3 of 6	2	NM_001277058.2	ENSP00000387966.2

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2362

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0683

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.0514

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00788

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0287

AC:

7219

AN:

251258

AF XY:

0.0237

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.0467

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.00797

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0135

AC:

19688

AN:

1461266

Hom.:

601

Cov.:

AF XY:

0.0127

AC XY:

9203

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

33468

American (AMR)

AF:

0.126

AC:

5647

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26114

East Asian (EAS)

AF:

0.0595

AC:

2358

AN:

39620

South Asian (SAS)

AF:

0.00437

AC:

377

AN:

86232

European-Finnish (FIN)

AF:

0.0241

AC:

1280

AN:

53200

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00808

AC:

8988

AN:

1111788

Other (OTH)

AF:

0.0135

AC:

813

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

973

1946

2919

3892

4865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

448

896

1344

1792

2240

<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:

0.0155

AC:

2366

AN:

152318

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1300

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00269

AC:

112

AN:

41572

American (AMR)

AF:

0.0684

AC:

1046

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.0517

AC:

268

AN:

5180

South Asian (SAS)

AF:

0.00807

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0297

AC:

315

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00788

AC:

536

AN:

68026

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

118

236

355

473

591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0111

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.0380

AC:

131

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00616

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2019

GeneDx

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

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

May 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

COFS syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

- -

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

-0.53

CADD

Benign

6.0

(source)

DANN

Benign

0.76

PhyloP100

-0.075

Mutation Taster

=72/28

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