rs762309206

chr19-45364832-CCTCA-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000400.4(ERCC2):c.594+2_594+5del variant causes a splice donor, splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000149 in 1,606,116 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ERCC2 NM_000400.4 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.44

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.050810337 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 8, new splice context is: ctgGTggga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• 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 19-45364832-CCTCA-C is Pathogenic according to our data. Variant chr19-45364832-CCTCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45364832-CCTCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.594+2_594+5del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.594+2_594+5del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_000400.4	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000758 AC: 19 AN: 250738 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135694

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 222 AN: 1453876 Hom.: 0 AF XY: 0.000146 AC XY: 106 AN XY: 723778

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	Observed in trans with a second ERCC2 variant in an individual with trichothiodystrophy (Viprakasit 2001); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; This variant is associated with the following publications: (PMID: 34426522, 31589614, 29754767, 11734544) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ERCC2: PVS1, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change affects a splice site in intron 7 of the ERCC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC2 are known to be pathogenic (PMID: 9238033, 11335038, 19085937, 19934020). This variant is present in population databases (rs762309206, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with trichothiodystrophy (PMID: 11734544). ClinVar contains an entry for this variant (Variation ID: 402226). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Xeroderma pigmentosum, group D Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with xeroderma pigmentosum, group D (MIM#278730). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotides are highly conserved. (SP) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as likely pathogenic in at least 5 individuals in relation to photosensitive trichothiodystrophy 1 (MIM#601675) and xeroderma pigmentosum, group D (MIM#278730) (ClinVar, HGMD, PMID: 11734544). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_000400.3(ERCC2): c.2047C>T; p.(Arg683Trp)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 04, 2015	- -

Xeroderma pigmentosum Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 20, 2023

Variant summary: ERCC2 c.594+2_594+5delTGAG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Four predict the variant creates a cryptic 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Punj_2018). The variant allele was found at a frequency of 7.6e-05 in 250738 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (7.6e-05 vs 0.00061), allowing no conclusion about variant significance. c.594+2_594+5delTGAG has been reported in the literature in individuals affected with Xeroderma Pigmentosum or Trichothiodystrophy, Acute lymphoblastic leukemia case, Hodgkin lymphoma (Mixed Cellularity), and Lung cancer (Viprakasit_2001, Punj_2018, Kim_2021, Mukherjee_2022). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitter (evaluation after 2014) cites this variant as pathogenic (n=1) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cerebrooculofacioskeletal syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 15, 2023

- -

Trichothiodystrophy 1, photosensitive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Dec 04, 2015

The c.594+2_594+5delTGAG splice-donor variant in the ERCC2 gene has not been previously reported. There has been a splice-donor variant in intron 7 of the ERCC2 gene observed in one affected individual with Trichothiodystrophy and was predicted to be a null allele. The affected individual was heterozygous for the splice-donor variant but also harbored a missense variant of unknown significance in the ERCC2 gene (Viprakasit et al., 2001). Although missense variants are a common mechanism for disease, loss of function variants have been reported in individuals affected with Xeroderma Pigmentosum. The c.594+2_594+5delTGAG splice-donor variant is present at a very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc). Computational algorithms predict evolutionary conservation at this locus and a loss of the splice-donor site resulting in intron retention and introduction of a premature termination codon. In summary, this collective evidence supports the provisional classification of the c.594+2_594+5delTGAG variant as Likely Pathogenic -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs762309206; hg19: chr19-45868090;