19-45476177-T-C

Variant names:

• chr19-45476177-T-C
• rs7256242
• ENST00000423698.6:c.-8+2559A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000423698.6(ERCC1):​c.-8+2559A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 151,952 control chromosomes in the GnomAD database, including 24,426 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24426 hom., cov: 31)
• Consequence: ERCC1 ENST00000423698.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.202
• Publications: 4 publications found

Genes affected

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ERCC1 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000423698.6	c.-8+2559A>G		intron_variant	Intron 1 of 8	2		ENSP00000394875.2

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84274 AN: 151836 Hom.: 24380 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.543

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.555 AC: 84367 AN: 151952 Hom.: 24426 Cov.: 31 AF XY: 0.555 AC XY: 41209 AN XY: 74270

African (AFR) AF: 0.726 AC: 30101 AN: 41444

American (AMR) AF: 0.518 AC: 7905 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1564 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2807 AN: 5176

South Asian (SAS) AF: 0.690 AC: 3323 AN: 4816

European-Finnish (FIN) AF: 0.403 AC: 4246 AN: 10526

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32722 AN: 67934

Other (OTH) AF: 0.544 AC: 1149 AN: 2112

Alfa AF: 0.516 Hom.: 5052

Bravo AF: 0.568

Asia WGS AF: 0.620 AC: 2157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.39
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7256242; hg19: chr19-45979435;