NM_000124.4:c.3284C>G

Variant names:

• chr10-49470676-G-C
• rs4253208
• NM_000124.4:c.3284C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000124.4(ERCC6):​c.3284C>G​(p.Pro1095Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,920 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1095A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (40 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 2.12
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035110116).
• BP6: Variant 10-49470676-G-C is Benign according to our data. Variant chr10-49470676-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1707.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1797/152238) while in subpopulation AFR AF = 0.0413 (1717/41538). AF 95% confidence interval is 0.0397. There are 39 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR,Unknown gene

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.3284C>G	p.Pro1095Arg	missense	Exon 18 of 21	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.3284C>G	p.Pro1095Arg	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.3284C>G	p.Pro1095Arg	missense	Exon 18 of 21	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.7668C>G		non_coding_transcript_exon	Exon 12 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*883C>G		non_coding_transcript_exon	Exon 8 of 11	ENSP00000485163.1	A0A096LNQ7

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1795 AN: 152120 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00299 AC: 750 AN: 251036 AF XY: 0.00203

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00124 AC: 1810 AN: 1461682 Hom.: 40 Cov.: 34 AF XY: 0.00106 AC XY: 768 AN XY: 727146

African (AFR) AF: 0.0466 AC: 1561 AN: 33476

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111972

Other (OTH) AF: 0.00238 AC: 144 AN: 60390

GnomAD4 genome AF: 0.0118 AC: 1797 AN: 152238 Hom.: 39 Cov.: 32 AF XY: 0.0107 AC XY: 800 AN XY: 74424

African (AFR) AF: 0.0413 AC: 1717 AN: 41538

American (AMR) AF: 0.00392 AC: 60 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.000618 Hom.: 1

Bravo AF: 0.0134

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00378 AC: 459

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	not specified (3)
-	1	1	Cockayne syndrome type 2 (2)
-	-	1	Age related macular degeneration 5 (1)
-	-	1	Cerebrooculofacioskeletal syndrome 1 (1)
-	-	1	DE SANCTIS-CACCHIONE SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.10
Sift	Benign	0.54	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.064
MVP		0.43
MPC		0.11
ClinPred		0.0061	T
GERP RS		1.2
Varity_R		0.018
gMVP		0.27
Mutation Taster		=97/3	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: rs4253208; hg19: chr10-50678722; COSMIC: COSV99054175; COSMIC: COSV99054175;