10-49483314-T-C

Position:

• chr10-49483314-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.1992+32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.903 in 1,607,482 control chromosomes in the GnomAD database, including 657,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57451 hom., cov: 33)
  • Exomes 𝑓: 0.91 (600221 hom.)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.836

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-49483314-T-C is Benign according to our data. Variant chr10-49483314-T-C is described in ClinVar as [Benign]. Clinvar id is 255163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.1992+32A>G		intron_variant		ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.1992+32A>G		intron_variant			NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.1992+32A>G		intron_variant		1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131529 AN: 152138 Hom.: 57430 Cov.: 33

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.904

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.887

GnomAD3 exomes AF: 0.913 AC: 229210 AN: 251038 Hom.: 105085 AF XY: 0.917 AC XY: 124397 AN XY: 135678

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.872

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.946

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.907

Gnomad OTH exome AF: 0.917

GnomAD4 exome AF: 0.908 AC: 1320691 AN: 1455224 Hom.: 600221 Cov.: 29 AF XY: 0.909 AC XY: 658259 AN XY: 724360

Gnomad4 AFR exome AF: 0.722

Gnomad4 AMR exome AF: 0.944

Gnomad4 ASJ exome AF: 0.872

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.926

Gnomad4 NFE exome AF: 0.906

Gnomad4 OTH exome AF: 0.897

GnomAD4 genome AF: 0.864 AC: 131598 AN: 152258 Hom.: 57451 Cov.: 33 AF XY: 0.870 AC XY: 64800 AN XY: 74482

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.924

Gnomad4 ASJ AF: 0.869

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.955

Gnomad4 FIN AF: 0.930

Gnomad4 NFE AF: 0.905

Gnomad4 OTH AF: 0.888

Alfa AF: 0.876 Hom.: 12048

Bravo AF: 0.857

Asia WGS AF: 0.964 AC: 3351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cerebrooculofacioskeletal syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cockayne syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.81

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: rs4253162; hg19: chr10-50691360;