rs2298881

Variant names:

• chr19-45423658-C-A
• rs2298881
• NM_001983.4:c.-8+123G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 109 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 -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 VariationId 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 rank	MANE	Protein	UniProt
ERCC1	NM_001983.4	c.-8+123G>T		intron_variant	Intron 1 of 9	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC1	ENST00000300853.8	c.-8+123G>T		intron_variant	Intron 1 of 9	1	NM_001983.4	ENSP00000300853.3

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

African (AFR) AF: 0.131 AC: 3343 AN: 25480

American (AMR) AF: 0.0927 AC: 1321 AN: 14254

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1964 AN: 15244

East Asian (EAS) AF: 0.421 AC: 10504 AN: 24922

South Asian (SAS) AF: 0.241 AC: 11846 AN: 49226

European-Finnish (FIN) AF: 0.154 AC: 2445 AN: 15894

Middle Eastern (MID) AF: 0.137 AC: 396 AN: 2898

European-Non Finnish (NFE) AF: 0.101 AC: 93881 AN: 929960

Other (OTH) AF: 0.131 AC: 5919 AN: 45032

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

African (AFR) AF: 0.129 AC: 5331 AN: 41368

American (AMR) AF: 0.0996 AC: 1512 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3462

East Asian (EAS) AF: 0.399 AC: 2039 AN: 5110

South Asian (SAS) AF: 0.255 AC: 1218 AN: 4782

European-Finnish (FIN) AF: 0.165 AC: 1741 AN: 10546

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7202 AN: 67960

Other (OTH) AF: 0.128 AC: 269 AN: 2098

Alfa AF: 0.105 Hom.: 675

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26056042, 18451256, 23166636, 22374244) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.52
PhyloP100		0.12
PromoterAI		-0.085	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2298881; hg19: chr19-45926916;