rs2298881

Positions:

• chr19-45423658-C-A
• chr19-45423658-C-G
• chr19-45423658-C-T

Variant summary

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

The NM_001983.4(ERCC1):​c.-8+123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,274,624 control chromosomes in the GnomAD database, including 11,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1572 hom., cov: 31)
  • Exomes 𝑓: 0.12 (9826 hom.)
• Consequence: ERCC1 NM_001983.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-45423658-C-A is Benign according to our data. Variant chr19-45423658-C-A is described in ClinVar as [Benign]. Clinvar id is 1227955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC1	NM_001983.4	c.-8+123G>T		intron_variant		ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8	c.-8+123G>T		intron_variant		1	NM_001983.4	ENSP00000300853	P1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19868 AN: 151594 Hom.: 1571 Cov.: 31

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.117 AC: 131619 AN: 1122910 Hom.: 9826 Cov.: 20 AF XY: 0.119 AC XY: 64025 AN XY: 535870

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0927

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.131 AC: 19869 AN: 151714 Hom.: 1572 Cov.: 31 AF XY: 0.136 AC XY: 10097 AN XY: 74106

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0996

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.128

Alfa AF: 0.104 Hom.: 569

Bravo AF: 0.123

Asia WGS AF: 0.300 AC: 1043 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 26056042, 18451256, 23166636, 22374244) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.52

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: rs2298881; hg19: chr19-45926916;