rs4253027

chr10-49530735-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000124.4(ERCC6):c.528A>G(p.Arg176=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,584 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R176R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (59 hom., cov: 32)
  • Exomes 𝑓: 0.013 (601 hom.)
• Consequence: ERCC6 NM_000124.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0750

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-49530735-T-C is Benign according to our data. Variant chr10-49530735-T-C is described in ClinVar as [Benign]. Clinvar id is 196213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49530735-T-C is described in Lovd as [Likely_benign]. Variant chr10-49530735-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.528A>G	p.Arg176=	synonymous_variant	3/21	ENST00000355832.10
ERCC6	NM_001277058.2	c.528A>G	p.Arg176=	synonymous_variant	3/6	ENST00000447839.7
ERCC6	NM_001346440.2	c.528A>G	p.Arg176=	synonymous_variant	3/21
ERCC6	NM_001277059.2	c.528A>G	p.Arg176=	synonymous_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.528A>G	p.Arg176=	synonymous_variant	3/21	1	NM_000124.4	P1
ERCC6	ENST00000447839.7	c.528A>G	p.Arg176=	synonymous_variant	3/6	2	NM_001277058.2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2362 AN: 152200 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0287 AC: 7219 AN: 251258 Hom.: 392 AF XY: 0.0237 AC XY: 3225 AN XY: 135820

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.0467

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.00797

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0135 AC: 19688 AN: 1461266 Hom.: 601 Cov.: 31 AF XY: 0.0127 AC XY: 9203 AN XY: 726946

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.0595

Gnomad4 SAS exome AF: 0.00437

Gnomad4 FIN exome AF: 0.0241

Gnomad4 NFE exome AF: 0.00808

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0155 AC: 2366 AN: 152318 Hom.: 59 Cov.: 32 AF XY: 0.0175 AC XY: 1300 AN XY: 74486

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.0684

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0517

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.0297

Gnomad4 NFE AF: 0.00788

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00835 Hom.: 16

Bravo AF: 0.0198

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00616

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

COFS syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cockayne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	6.0
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs4253027; hg19: chr10-50738781; COSMIC: COSV63390177;