rs61760163

Variant names:

• chr10-49482860-G-A
• rs61760163
• NM_000124.4:c.1996C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP3 BP4_Strong BP6 BS1 BS2

The NM_000124.4(ERCC6):​c.1996C>T​(p.Arg666Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,958 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R666H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:9
• Conservation: PhyloP100: 8.15
• Publications: 16 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 176) in uniprot entity ERCC6_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_000124.4
• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.054732054).
• BP6: Variant 10-49482860-G-A is Benign according to our data. Variant chr10-49482860-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190156.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00176 (267/152128) while in subpopulation NFE AF = 0.00282 (192/67990). AF 95% confidence interval is 0.0025. There are 0 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.1996C>T	p.Arg666Cys	missense_variant	Exon 10 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.1996C>T	p.Arg666Cys	missense_variant	Exon 10 of 21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.1996C>T	p.Arg666Cys	missense_variant	Exon 10 of 21	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000851

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00177 AC: 444 AN: 251352 AF XY: 0.00158

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00224 AC: 3278 AN: 1461830 Hom.: 4 Cov.: 31 AF XY: 0.00208 AC XY: 1512 AN XY: 727212

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00288 AC: 129 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00255 AC: 2839 AN: 1111970

Other (OTH) AF: 0.00283 AC: 171 AN: 60392

GnomAD4 genome AF: 0.00176 AC: 267 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.00168 AC XY: 125 AN XY: 74362

African (AFR) AF: 0.000530 AC: 22 AN: 41504

American (AMR) AF: 0.00255 AC: 39 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.000851 AC: 9 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 67990

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00204 Hom.: 1

Bravo AF: 0.00188

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00163 AC: 198

EpiCase AF: 0.00234

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERCC6: PP3, BS1, BS2 -

Mar 16, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ERCC6 p.Arg666Cys variant was identified in the literature in 1 of 28 proband chromosomes (frequency: 0.036) from individuals with a positive history of cancer (proband had colon cancer) (Castellanos_2017_PMID:28051113). The variant was identified in dbSNP (ID: rs61760163), LOVD 3.0 and ClinVar (classified as likely benign by Invitae and Illumina, and as uncertain significance by Claritas Genomics, Genetic Services Laboratory University of Chicago, Fulgent Genetics, EGL Genetic Diagnostics and GeneDx). The variant was identified in control databases in 498 of 282720 chromosomes (1 homozygous) at a frequency of 0.001761 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 103 of 35438 chromosomes (freq: 0.002906), Other in 20 of 7220 chromosomes (freq: 0.00277), European (non-Finnish) in 318 of 129064 chromosomes (freq: 0.002464), Ashkenazi Jewish in 22 of 10368 chromosomes (freq: 0.002122), African in 16 of 24964 chromosomes (freq: 0.000641), European (Finnish) in 16 of 25116 chromosomes (freq: 0.000637) and South Asian in 3 of 30614 chromosomes (freq: 0.000098), but was not observed in the East Asian population. The p.Arg666 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with colorectal or other cancer (PMID: 28051113, 28050010, 29602769); Reported previously as a likely pathogenic variant in patients with primary ovarian insufficiency (PMID: 36099812); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29784668, 28051113, 29602769, 28050010, 30653986, 34513715, 36099812) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 17, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:2 Benign:1

Jan 06, 2014

Claritas Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0684249:Lung carcinoma;C0751038:Cockayne syndrome type 2;C3151063:Age related macular degeneration 5;C3551173:UV-sensitive syndrome 1;C4310783:Premature ovarian failure 11 Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COFS syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 12, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cone-rod dystrophy Benign:1

Oct 18, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Benign:1

Nov 26, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cockayne syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.055	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.90
MPC		0.59
ClinPred		0.037	T
GERP RS		5.6
Varity_R		0.41
gMVP		0.80
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs61760163; hg19: chr10-50690906; COSMIC: COSV63389278; COSMIC: COSV63389278;