rs171140

Variant names:

• chr19-45361744-C-A
• rs171140
• NM_000400.4:c.1119-102G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.1119-102G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 868,646 control chromosomes in the GnomAD database, including 147,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32321 hom., cov: 31)
  • Exomes 𝑓: 0.56 (115287 hom.)
• Consequence: ERCC2 NM_000400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.161
• Publications: 31 publications found

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• trichothiodystrophy 1, photosensitive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• sarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  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=-0.92).
• BP6: Variant 19-45361744-C-A is Benign according to our data. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45361744-C-A is described in CliVar as Benign. Clinvar id is 135529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1119-102G>T		intron_variant	Intron 11 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1119-102G>T		intron_variant	Intron 11 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96572 AN: 151800 Hom.: 32270 Cov.: 31

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.595

GnomAD2 exomes AF: 0.581 AC: 117148 AN: 201574 AF XY: 0.579

Gnomad AFR exome AF: 0.870

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.511

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.564 AC: 404426 AN: 716726 Hom.: 115287 Cov.: 9 AF XY: 0.566 AC XY: 215607 AN XY: 380928

African (AFR) AF: 0.861 AC: 16455 AN: 19108

American (AMR) AF: 0.516 AC: 19499 AN: 37762

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 12435 AN: 20744

East Asian (EAS) AF: 0.491 AC: 16823 AN: 34230

South Asian (SAS) AF: 0.603 AC: 41386 AN: 68666

European-Finnish (FIN) AF: 0.593 AC: 28093 AN: 47356

Middle Eastern (MID) AF: 0.588 AC: 2515 AN: 4280

European-Non Finnish (NFE) AF: 0.550 AC: 246954 AN: 449244

Other (OTH) AF: 0.574 AC: 20266 AN: 35336

GnomAD4 genome AF: 0.636 AC: 96676 AN: 151920 Hom.: 32321 Cov.: 31 AF XY: 0.634 AC XY: 47050 AN XY: 74248

African (AFR) AF: 0.861 AC: 35652 AN: 41426

American (AMR) AF: 0.528 AC: 8050 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2039 AN: 3470

East Asian (EAS) AF: 0.498 AC: 2566 AN: 5152

South Asian (SAS) AF: 0.588 AC: 2836 AN: 4826

European-Finnish (FIN) AF: 0.593 AC: 6259 AN: 10546

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37322 AN: 67934

Other (OTH) AF: 0.594 AC: 1253 AN: 2108

Alfa AF: 0.583 Hom.: 74781

Bravo AF: 0.643

Asia WGS AF: 0.561 AC: 1956 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

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

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.5
DANN	Benign	0.52
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs171140; hg19: chr19-45865002; COSMIC: COSV55538511; COSMIC: COSV55538511;