chr10-49532830-G-C

Position:

• chr10-49532830-G-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.135C>G​(p.Leu45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,613,926 control chromosomes in the GnomAD database, including 421,790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32467 hom., cov: 31)
  • Exomes 𝑓: 0.73 (389323 hom.)
• Consequence: ERCC6 NM_000124.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.160

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=-0.89).
• BP6: Variant 10-49532830-G-C is Benign according to our data. Variant chr10-49532830-G-C is described in ClinVar as [Benign]. Clinvar id is 129014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49532830-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.135C>G	p.Leu45=	synonymous_variant	2/21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2	c.135C>G	p.Leu45=	synonymous_variant	2/6	ENST00000447839.7	NP_001263987.1
ERCC6	NM_001346440.2	c.135C>G	p.Leu45=	synonymous_variant	2/21		NP_001333369.1
ERCC6	NM_001277059.2	c.135C>G	p.Leu45=	synonymous_variant	2/6		NP_001263988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.135C>G	p.Leu45=	synonymous_variant	2/21	1	NM_000124.4	ENSP00000348089	P1
ERCC6	ENST00000447839.7	c.135C>G	p.Leu45=	synonymous_variant	2/6	2	NM_001277058.2	ENSP00000387966

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96300 AN: 151930 Hom.: 32459 Cov.: 31

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.692

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.657

GnomAD3 exomes AF: 0.698 AC: 175379 AN: 251408 Hom.: 62762 AF XY: 0.715 AC XY: 97154 AN XY: 135886

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.714

Gnomad EAS exome AF: 0.528

Gnomad SAS exome AF: 0.807

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.726 AC: 1061467 AN: 1461878 Hom.: 389323 Cov.: 115 AF XY: 0.730 AC XY: 531050 AN XY: 727240

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.712

Gnomad4 EAS exome AF: 0.551

Gnomad4 SAS exome AF: 0.806

Gnomad4 FIN exome AF: 0.762

Gnomad4 NFE exome AF: 0.740

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.634 AC: 96324 AN: 152048 Hom.: 32467 Cov.: 31 AF XY: 0.641 AC XY: 47654 AN XY: 74314

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.534

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.741

Gnomad4 OTH AF: 0.659

Alfa AF: 0.711 Hom.: 12721

Bravo AF: 0.611

Asia WGS AF: 0.656 AC: 2280 AN: 3478

EpiCase AF: 0.752

EpiControl AF: 0.751

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Claritas Genomics	Apr 17, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

COFS syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebrooculofacioskeletal syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cockayne syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cockayne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

UV-sensitive syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

DE SANCTIS-CACCHIONE SYNDROME Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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	-0.89
CADD	Benign	0.91
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2228524; hg19: chr10-50740876; COSMIC: COSV63390329; COSMIC: COSV63390329;