NM_000124.4:c.4238A>G

Variant names:

• chr10-49459059-T-C
• rs2228529
• NM_000124.4:c.4238A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.4238A>G​(p.Gln1413Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,614,064 control chromosomes in the GnomAD database, including 37,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1413Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3281 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34474 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.104
• Publications: 57 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)

ENSG00000235939 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003504604).
• BP6: Variant 10-49459059-T-C is Benign according to our data. Variant chr10-49459059-T-C is described in ClinVar as Benign. ClinVar VariationId is 129020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.4238A>G	p.Gln1413Arg	missense	Exon 21 of 21	NP_000115.1
	ERCC6	NM_001346440.2		c.4238A>G	p.Gln1413Arg	missense	Exon 21 of 21	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.4238A>G	p.Gln1413Arg	missense	Exon 21 of 21	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.8622A>G		non_coding_transcript_exon	Exon 15 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*1837A>G		non_coding_transcript_exon	Exon 11 of 11	ENSP00000485163.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29433 AN: 152058 Hom.: 3277 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.217 AC: 54373 AN: 251060 AF XY: 0.228

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0523

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.210 AC: 306607 AN: 1461890 Hom.: 34474 Cov.: 34 AF XY: 0.215 AC XY: 156589 AN XY: 727246

African (AFR) AF: 0.119 AC: 3993 AN: 33480

American (AMR) AF: 0.176 AC: 7853 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6826 AN: 26136

East Asian (EAS) AF: 0.0533 AC: 2116 AN: 39700

South Asian (SAS) AF: 0.346 AC: 29815 AN: 86258

European-Finnish (FIN) AF: 0.268 AC: 14317 AN: 53420

Middle Eastern (MID) AF: 0.263 AC: 1517 AN: 5768

European-Non Finnish (NFE) AF: 0.205 AC: 227612 AN: 1112008

Other (OTH) AF: 0.208 AC: 12558 AN: 60396

GnomAD4 genome AF: 0.193 AC: 29445 AN: 152174 Hom.: 3281 Cov.: 32 AF XY: 0.201 AC XY: 14952 AN XY: 74396

African (AFR) AF: 0.123 AC: 5103 AN: 41536

American (AMR) AF: 0.208 AC: 3178 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3468

East Asian (EAS) AF: 0.0518 AC: 268 AN: 5178

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4820

European-Finnish (FIN) AF: 0.283 AC: 2989 AN: 10578

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14668 AN: 67986

Other (OTH) AF: 0.210 AC: 444 AN: 2110

Alfa AF: 0.208 Hom.: 8533

Bravo AF: 0.178

TwinsUK AF: 0.204 AC: 758

ALSPAC AF: 0.192 AC: 739

ESP6500AA AF: 0.135 AC: 596

ESP6500EA AF: 0.217 AC: 1864

ExAC AF: 0.218 AC: 26450

Asia WGS AF: 0.180 AC: 628 AN: 3478

EpiCase AF: 0.219

EpiControl AF: 0.218

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Jun 29, 2012

Claritas Genomics

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

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 15, 2016

Eurofins Ntd Llc (ga)

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

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 22, 2018

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.1
DANN	Benign	0.62
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.10
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.51	T
Sift4G	Benign	0.49	T
Polyphen		0.13	B
Vest4		0.034
MPC		0.12
ClinPred		0.0011	T
GERP RS		-4.9
Varity_R		0.023
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

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: rs2228529; hg19: chr10-50667105; COSMIC: COSV63389074; COSMIC: COSV63389074;