rs2228528

Variant names:

• chr10-49524234-C-T
• rs2228528
• NM_000124.4:c.1196G>A

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.1196G>A​(p.Gly399Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,894 control chromosomes in the GnomAD database, including 27,994 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2775 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25219 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.139
• Publications: 73 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]

PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, 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. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4212728E-4).
• BP6: Variant 10-49524234-C-T is Benign according to our data. Variant chr10-49524234-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 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.1196G>A	p.Gly399Asp	missense	Exon 5 of 21	NP_000115.1
	ERCC6	NM_001277058.2	MANE Plus Clinical	c.1196G>A	p.Gly399Asp	missense	Exon 5 of 6	NP_001263987.1
	ERCC6	NM_001346440.2		c.1196G>A	p.Gly399Asp	missense	Exon 5 of 21	NP_001333369.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1196G>A	p.Gly399Asp	missense	Exon 5 of 21	ENSP00000348089.5
	ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.1196G>A	p.Gly399Asp	missense	Exon 5 of 6	ENSP00000387966.2
	ERCC6	ENST00000898255.1		c.1196G>A	p.Gly399Asp	missense	Exon 5 of 21	ENSP00000568314.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27169 AN: 151926 Hom.: 2773 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.202 AC: 50252 AN: 248904 AF XY: 0.192

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.471

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.176 AC: 256860 AN: 1461850 Hom.: 25219 Cov.: 33 AF XY: 0.174 AC XY: 126222 AN XY: 727220

African (AFR) AF: 0.167 AC: 5581 AN: 33480

American (AMR) AF: 0.293 AC: 13100 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4099 AN: 26134

East Asian (EAS) AF: 0.449 AC: 17825 AN: 39700

South Asian (SAS) AF: 0.139 AC: 11998 AN: 86258

European-Finnish (FIN) AF: 0.164 AC: 8748 AN: 53406

Middle Eastern (MID) AF: 0.165 AC: 954 AN: 5766

European-Non Finnish (NFE) AF: 0.165 AC: 183649 AN: 1112006

Other (OTH) AF: 0.181 AC: 10906 AN: 60394

GnomAD4 genome AF: 0.179 AC: 27188 AN: 152044 Hom.: 2775 Cov.: 32 AF XY: 0.179 AC XY: 13269 AN XY: 74328

African (AFR) AF: 0.167 AC: 6943 AN: 41496

American (AMR) AF: 0.220 AC: 3357 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 536 AN: 3468

East Asian (EAS) AF: 0.464 AC: 2380 AN: 5130

South Asian (SAS) AF: 0.142 AC: 684 AN: 4816

European-Finnish (FIN) AF: 0.160 AC: 1691 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11016 AN: 67954

Other (OTH) AF: 0.184 AC: 389 AN: 2112

Alfa AF: 0.173 Hom.: 11138

Bravo AF: 0.187

TwinsUK AF: 0.169 AC: 625

ALSPAC AF: 0.180 AC: 692

ESP6500AA AF: 0.165 AC: 729

ESP6500EA AF: 0.161 AC: 1382

ExAC AF: 0.196 AC: 23759

Asia WGS AF: 0.296 AC: 1029 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.155

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Cerebrooculofacioskeletal syndrome 1 (1)
-	-	1	Cockayne syndrome (1)
-	-	1	Cockayne syndrome type 2 (1)
-	-	1	COFS syndrome (1)
-	-	1	DE SANCTIS-CACCHIONE SYNDROME (1)
-	-	1	Macular degeneration (1)
-	-	1	UV-sensitive syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.050
DANN	Benign	0.50
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.37	N
PhyloP100		0.14
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.013
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.019
MPC		0.13
ClinPred		0.00046	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.017
gMVP		0.11
Mutation Taster		=97/3	polymorphism (auto)

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: rs2228528; hg19: chr10-50732280; COSMIC: COSV63388139; COSMIC: COSV63388139;