10-49482809-G-C

Variant names:

• chr10-49482809-G-C
• rs121917904
• NM_000124.4:c.2047C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000124.4(ERCC6):​c.2047C>G​(p.Arg683Gly) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R683Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000124.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

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.2047C>G	p.Arg683Gly	missense	Exon 10 of 21	NP_000115.1
	ERCC6	NM_001346440.2		c.2047C>G	p.Arg683Gly	missense	Exon 10 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.2047C>G	p.Arg683Gly	missense	Exon 10 of 21	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.6527C>G		non_coding_transcript_exon	Exon 5 of 15
	ERCC6	ENST00000681659.1		c.1888C>G	p.Arg630Gly	missense	Exon 9 of 20	ENSP00000505631.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2047C>G (p.R683G) alteration is located in exon 10 (coding exon 9) of the ERCC6 gene. This alteration results from a C to G substitution at nucleotide position 2047, causing the arginine (R) at amino acid position 683 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.75	N
PhyloP100		5.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.64
MutPred		0.55		Gain of helix (P = 0.062)
MVP		0.84
MPC		0.22
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.63
Mutation Taster		=52/48	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: rs121917904; hg19: chr10-50690855;