rs2228525

Variant names:

• chr10-49472913-G-A
• rs2228525
• NM_000124.4:c.2825C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-49472913-G-A
• chr10-49472913-G-C

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.2825C>T​(p.Thr942Met) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,613,828 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T942P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (41 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.89
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015826166).
• BP6: Variant 10-49472913-G-A is Benign according to our data. Variant chr10-49472913-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 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.2825C>T	p.Thr942Met	missense	Exon 15 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.2825C>T	p.Thr942Met	missense	Exon 15 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.2825C>T	p.Thr942Met	missense	Exon 15 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.7209C>T		non_coding_transcript_exon	Exon 9 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*424C>T		non_coding_transcript_exon	Exon 5 of 11	ENSP00000485163.1	A0A096LNQ7

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2213 AN: 152080 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00395 AC: 991 AN: 250968 AF XY: 0.00303

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00167 AC: 2435 AN: 1461630 Hom.: 41 Cov.: 33 AF XY: 0.00144 AC XY: 1050 AN XY: 727110

African (AFR) AF: 0.0521 AC: 1742 AN: 33464

American (AMR) AF: 0.00369 AC: 165 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86192

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53406

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1111910

Other (OTH) AF: 0.00401 AC: 242 AN: 60382

GnomAD4 genome AF: 0.0146 AC: 2223 AN: 152198 Hom.: 47 Cov.: 33 AF XY: 0.0138 AC XY: 1028 AN XY: 74412

African (AFR) AF: 0.0494 AC: 2049 AN: 41508

American (AMR) AF: 0.00778 AC: 119 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68028

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00566 Hom.: 43

Bravo AF: 0.0170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0488 AC: 215

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00506 AC: 614

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Age related macular degeneration 5 (1)
-	-	1	Cerebrooculofacioskeletal syndrome 1 (1)
-	-	1	Cockayne syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.96	N
PhyloP100		6.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.35
Sift	Benign	0.25	T
Sift4G	Benign	0.28	T
Polyphen		0.99	D
Vest4		0.37
MVP		0.66
MPC		0.17
ClinPred		0.039	T
GERP RS		3.9
Varity_R		0.067
gMVP		0.73
Mutation Taster		=67/33	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: rs2228525; hg19: chr10-50680959; COSMIC: COSV100876368; COSMIC: COSV100876368;