rs776705174

Variant names:

• chr19-45357267-C-CA
• rs776705174
• NM_000400.4:c.1479+2dupT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000400.4(ERCC2):​c.1479+2dupT variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000472 in 1,609,106 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ERCC2 NM_000400.4 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 5.97
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.044678055 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45357267-C-CA is Pathogenic according to our data. Variant chr19-45357267-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 329511.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1479+2dupT		splice_donor_variant, intron_variant	Intron 15 of 22	ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1479+2_1479+3insT		splice_donor_variant, intron_variant	Intron 15 of 22	1	NM_000400.4	ENSP00000375809.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248778 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 73 AN: 1456900 Hom.: 0 Cov.: 30 AF XY: 0.0000455 AC XY: 33 AN XY: 725008

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.0000650 AC: 72 AN: 1107988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60172

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ERCC2-related disorder Pathogenic:2 Uncertain:1

Apr 22, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000400.3(ERCC2):c.1479+2dupT is a variant in a canonical splice site classified as likely pathogenic in the context of ERCC2-related disorders. c.1479+2dupT has been observed in cases with relevant disease (PMID: 7920640, 35615778, 39976384). Functional assessments of this variant are available in the literature (PMID: 7920640). c.1479+2dupT has been observed in referenced population frequency databases. In summary, NM_000400.3(ERCC2):c.1479+2dupT is a variant in a canonical splice site that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1479+2dupT variant is reported in one study in which it was found in two unrelated individuals with trichothiodystrophy who were both compound heterozygous for the c.1479+2dupT variant, one with a deletion variant on the second allele and one with a missense variant (Broughton et al. 1994). Both individuals displayed a DNA repair deficiency. Control data are not available for this variant, which is reported at a frequency of 0.00002 in the European (Non-Finnish) population of the Exome Aggregation Consortium database. This frequency is based on one allele only so the variant is presumed to be rare. RT-PCR studies showed an 18 bp deletion due to the c.1479+2dupT variant resulting in an in-frame loss of six amino acids in exon 15. Based on the limited evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for ERCC2-related disorders.

Aug 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ERCC2 c.1479+2dupT variant is predicted to result in an intronic duplication. This variant was reported in the compound heterozygous state in two unrelated individuals with ERCC2-related disorders. RT-PCR studies derived from patients harboring this variant revealed two aberrant transcripts, one containing an 18bp deletion resulting in loss of amino acids 488-493 at the 3' end of exon 15 and another containing a 102bp deletion resulting in loss of amino acids 460-493 corresponding to exon 15 (described as +T insertion in the splice donor site of intron 15 in Broughton et al 1994. PubMed ID: 7920640). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Xeroderma pigmentosum Pathogenic:2

Apr 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1479+2dupT variant in ERCC2 has been reported in 2 individuals with Xerode rma pigmentosum, including in trans with a truncating allele in one individual ( Broughton 1994), and has been reported in ClinVar (Variation ID: 329511). The va riant has been identified in 2/110536 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs776705174). Pl ease note that for diseases with clinical variability, reduced penetrance, or re cessive inheritance, pathogenic variants may be present at a low frequency in th e general population. This variant occurs in the invariant region (+/- 1,2) of t he splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro data suggest this variant results in the deletion of 18 nucleotides, corresponding to an in-frame deletion. In summar y, although additional studies are required to fully establish its clinical sign ificance, the c.1479+2dupT variant is likely pathogenic. ACMG/AMP Criteria appli ed: PM2; PM3; PM4.

Feb 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ERCC2 c.1479+2dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site and one predicts the variant weakens the canonical 5' donor site. This variant has been found to affect mRNA splicing, resulting in loss of exon 15 or the last 18 nucleotides of exon 15 due to use of a cryptic splice site (Broughton_1994). The variant allele was found at a frequency of 4e-06 in 248778 control chromosomes (gnomAD). c.1479+2dupT has been reported in the literature in individuals affected with trichothiodystrophy (Broughton_1994). These data indicate that the variant may be associated with disease. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided Pathogenic:2

Oct 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing. Functional studies have demonstrated two mRNA products are created; one with loss of exon 15 and another with an 18bp deletion due to use of a cryptic site (Broughton et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 7920640, 31980526)

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 15 of the ERCC2 gene. It does not directly change the encoded amino acid sequence of the ERCC2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs776705174, gnomAD 0.002%). This variant has been observed in individual(s) with trichothiodystrophy (PMID: 7920640). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as +T insertion in splice donor site of intron 15. ClinVar contains an entry for this variant (Variation ID: 329511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cerebrooculofacioskeletal syndrome 2 Pathogenic:1

Feb 09, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: 21

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

Other links and lift over

dbSNP: rs776705174; hg19: chr19-45860525;