chr19-45357267-C-CA

Position:

• chr19-45357267-C-CA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000400.4(ERCC2):​c.1479+2_1479+3insT variant causes a splice region, 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_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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 id is 329511.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC2	NM_000400.4	c.1479+2_1479+3insT		splice_region_variant, intron_variant		ENST00000391945.10	NP_000391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10	c.1479+2_1479+3insT		splice_region_variant, intron_variant		1	NM_000400.4	ENSP00000375809	P1

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

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248778 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134540

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000650

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 04, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	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) -

ERCC2-related disorder Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 01, 2024	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. -

Cerebrooculofacioskeletal syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs776705174; hg19: chr19-45860525;