rs368728467

Variant names:

• chr10-49474074-A-G
• rs368728467
• NM_000124.4:c.2551T>C

Your query was ambiguous. Multiple possible variants found:

• chr10-49474074-A-G
• chr10-49474074-A-T

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000124.4(ERCC6):​c.2551T>C​(p.Trp851Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001228424: Experimental studies have shown that this missense change affects ERCC6 function (PMID:9443879, 20122405, 25820262, 29203878)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.32
• Publications: 11 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)

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_000124.4 (ERCC6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001228424: Experimental studies have shown that this missense change affects ERCC6 function (PMID: 9443879, 20122405, 25820262, 29203878).; SCV002103347: Functional studies report experimental evidence evaluating an impact on protein function and this variant results in impaired in its ability to associate with chromatin in response to UV irradiation, failed to suppress the increase in 53BP1 and Rif1 damage foci formation in CSB-knockout cells and failed to recruit BRCA1 (Mallery_1998, Lake_2010, Batenburg_2015, Batenburg_2019).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 10-49474074-A-G is Pathogenic according to our data. Variant chr10-49474074-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 210955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2551T>C	p.Trp851Arg	missense	Exon 13 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.2551T>C	p.Trp851Arg	missense	Exon 13 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.2551T>C	p.Trp851Arg	missense	Exon 13 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.6935T>C		non_coding_transcript_exon	Exon 7 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*150T>C		non_coding_transcript_exon	Exon 3 of 11	ENSP00000485163.1	A0A096LNQ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000506 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cockayne syndrome type 2 (2)
-	1	-	Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2 (1)
1	-	-	Cockayne syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of disorder (P = 0.0253)
MVP		0.94
MPC		0.69
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs368728467; hg19: chr10-50682120;