rs2228526

Variant names:

• chr10-49470671-T-C
• rs2228526
• NM_000124.4:c.3289A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.3289A>G​(p.Met1097Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,762 control chromosomes in the GnomAD database, including 37,824 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3321 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34503 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.201
• Publications: 79 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: Orphanet, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
• 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 -16 ACMG points.

• BP6: Variant 10-49470671-T-C is Benign according to our data. Variant chr10-49470671-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129016.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.3289A>G	p.Met1097Val	missense	Exon 18 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.3289A>G	p.Met1097Val	missense	Exon 18 of 21	NP_001333369.1	Q03468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.3289A>G	p.Met1097Val	missense	Exon 18 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.7673A>G		non_coding_transcript_exon	Exon 12 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*888A>G		non_coding_transcript_exon	Exon 8 of 11	ENSP00000485163.1	A0A096LNQ7

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29692 AN: 152042 Hom.: 3317 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.217 AC: 54486 AN: 251018 AF XY: 0.229

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0523

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.210 AC: 306775 AN: 1461602 Hom.: 34503 Cov.: 35 AF XY: 0.215 AC XY: 156659 AN XY: 727120

African (AFR) AF: 0.124 AC: 4166 AN: 33478

American (AMR) AF: 0.176 AC: 7871 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6824 AN: 26132

East Asian (EAS) AF: 0.0533 AC: 2116 AN: 39686

South Asian (SAS) AF: 0.346 AC: 29811 AN: 86244

European-Finnish (FIN) AF: 0.268 AC: 14275 AN: 53292

Middle Eastern (MID) AF: 0.263 AC: 1518 AN: 5766

European-Non Finnish (NFE) AF: 0.205 AC: 227621 AN: 1111896

Other (OTH) AF: 0.208 AC: 12573 AN: 60388

GnomAD4 genome AF: 0.195 AC: 29705 AN: 152160 Hom.: 3321 Cov.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74372

African (AFR) AF: 0.129 AC: 5370 AN: 41528

American (AMR) AF: 0.208 AC: 3181 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3470

East Asian (EAS) AF: 0.0515 AC: 267 AN: 5184

South Asian (SAS) AF: 0.347 AC: 1670 AN: 4810

European-Finnish (FIN) AF: 0.282 AC: 2984 AN: 10570

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

European-Non Finnish (NFE) AF: 0.216 AC: 14667 AN: 67994

Other (OTH) AF: 0.210 AC: 443 AN: 2110

Alfa AF: 0.206 Hom.: 13691

Bravo AF: 0.180

TwinsUK AF: 0.204 AC: 756

ALSPAC AF: 0.191 AC: 737

ESP6500AA AF: 0.140 AC: 619

ESP6500EA AF: 0.217 AC: 1864

ExAC AF: 0.218 AC: 26533

Asia WGS AF: 0.181 AC: 629 AN: 3478

EpiCase AF: 0.219

EpiControl AF: 0.218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	1	Cockayne syndrome (1)
-	-	1	COFS syndrome (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.1
DANN	Benign	0.64
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.20
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.14
Sift	Benign	0.52	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.063
MPC		0.10
ClinPred		0.00087	T
GERP RS		-6.2
Varity_R		0.022
gMVP		0.21
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2228526; hg19: chr10-50678717; COSMIC: COSV63389091; COSMIC: COSV63389091;