19-45352249-G-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000400.4(ERCC2):āc.2150C>Gā(p.Ala717Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.00027 ( 0 hom., cov: 32)
Exomes š: 0.00046 ( 0 hom. )
Consequence
ERCC2
NM_000400.4 missense
NM_000400.4 missense
Scores
15
4
Clinical Significance
Conservation
PhyloP100: 9.00
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 19-45352249-G-C is Pathogenic according to our data. Variant chr19-45352249-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ERCC2 | NM_000400.4 | c.2150C>G | p.Ala717Gly | missense_variant | 22/23 | ENST00000391945.10 | NP_000391.1 | |
| ERCC2 | XM_011526611.3 | c.2072C>G | p.Ala691Gly | missense_variant | 21/22 | XP_011524913.1 | ||
| ERCC2 | XR_001753633.3 | n.2183C>G | non_coding_transcript_exon_variant | 22/24 | ||||
| ERCC2 | XR_007066680.1 | n.2105C>G | non_coding_transcript_exon_variant | 21/23 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ERCC2 | ENST00000391945.10 | c.2150C>G | p.Ala717Gly | missense_variant | 22/23 | 1 | NM_000400.4 | ENSP00000375809 | P1 |
Frequencies
GnomAD3 genomes 0.000269 AC: 41AN: 152162Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
41
AN:
152162
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000314 AC: 79AN: 251244Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135838
GnomAD3 exomes
AF:
AC:
79
AN:
251244
Hom.:
AF XY:
AC XY:
45
AN XY:
135838
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000465 AC: 679AN: 1461776Hom.: 0 Cov.: 33 AF XY: 0.000451 AC XY: 328AN XY: 727184
GnomAD4 exome
AF:
AC:
679
AN:
1461776
Hom.:
Cov.:
33
AF XY:
AC XY:
328
AN XY:
727184
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000269 AC: 41AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74334
GnomAD4 genome
AF:
AC:
41
AN:
152162
Hom.:
Cov.:
32
AF XY:
AC XY:
15
AN XY:
74334
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
4
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
42
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group D Pathogenic:3Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in ERCC2 is predicted to replace alanine with glycine at codon 717, p.(Ala717Gly). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in a helical region. There is a moderate physicochemical difference between alanine and glycine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.2% (23/10,368 alleles) in the Ashkenazi Jewish population, whereas the highest continental population minor allele frequency is 0.04% (47/128,994 alleles) in the European non-Finnish) population. This is consistent with recessive disease. This variant has been detected (always in cis with c.1381C>G, p.Leu461Val) in at least nine individuals with milder/adult-onset xeroderma pigmentosum-Cockayne syndrome complex, trichothiodystrophy, or xeroderma pigmentosum (XP). Of those individuals, five were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by parental/family testing or other methods (PMID: 9195225, 15982307, 16135823, 23232694, 26884178, 35699229). XP complementation analysis was conducted in the cells of most of these individuals, and the XP-D complementation group was identified, which is highly specific for ERCC2-related XP. Multiple lines of computational evidence predict an impact on splicing (SpliceAI, MaxEntScan, NNSplice), and have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). This splice prediction is confirmed by allele-specific RT-PCR. The assay demonstrated that the variant impacts splicing by activation of a leaky cryptic donor site leading to a 55 bp deletion in exon 22 (r.[2146_2190del,2150c>g] p.[Val716_Arg730del,Ala717Gly]; PMID: 25716912). In vitro nucleotide excision repair (NER) and transcription assays in NER-deficient cell lines showed p.Val716_Arg730del exhibited defective repair and transcriptional activity, while p.Ala717Gly exhibited efficient repair and transcriptional activity. The combined p.[Leu461Val;Ala717Gly] exhibited intermediate activity (PMID: 25716912). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Supporting, PM2_Supporting, PP3, PP4. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 13, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5. - |
not provided Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | ERCC2: PS3, PM2, PM3, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 717 of the ERCC2 protein (p.Ala717Gly). This variant is present in population databases (rs144564120, gnomAD 0.2%). This missense change has been observed in individuals with breast and ovarian cancer and xeroderma pigmentosum and trichothiodystrophy (PMID: 15982307, 23232694, 25716912, 26884178, 27504877, 29607586). This variant is also known as del 716āĆƬ730 or g.18339C>G. ClinVar contains an entry for this variant (Variation ID: 134102). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 7585650, 15982307, 25716912). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2022 | Published functional studies demonstrate a damaging effect, specifically, RNA studies suggest the missense variant creates a cryptic splice donor site upstream of the natural splice site, leading to an in-frame deletion of 15 amino acids (Takayama et al., 1995), and the A717G;L461V complex allele demonstrated a reduced TFIIH binding capacity with partial NER activity, as compared to wild-type (Horibata et al., 2015); Reported in multiple unrelated individuals on the same allele (in cis) with the L461V variant of uncertain significance (Takayama et al., 1995; Takayama et al., 1997; Orioli et al., 2013; Horibata et al., 2015; Fassihi et al. 2016); This variant is associated with the following publications: (PMID: 22234153, 24728327, 23232694, 15982307, 17020410, 27504877, 7585650, 30676620, 8571952, 16135823, 23221806, 26884178, 25716912, 9195225, 29607586, 31980526, 34426522, 31589614, 33726816) - |
Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jan 20, 2016 | - - |
Xeroderma pigmentosum Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 04, 2023 | Variant summary: ERCC2 c.2150C>G (p.Ala717Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. It has always been reported in cis with c.1381C>G (p.Leu461Val). Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in splicing-out of the last 45 bases of exon 22 resulting in r.[1381c>g;2146_2190del], which is translated into p.[L461V;V716_R730del] (Horibata_2015). The variant allele was found at a frequency of 0.00031 in 251244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum/Trichothiodystrophy (0.00031 vs 0.00061), allowing no conclusion about variant significance. c.2150C>G has been reported in the literature always a complex allele in cis with c.1381C>G (p.Leu461Val) in compound heterozygous genotypes with other pathogenic alleles in multiple individuals with features of Xeroderma Pigmentosum and Trichothiodystrophy (example, Takayama_1996, Moslehi_2012, Fujimoto_2005, Zhou_2013, Fassihi_2016, Horibata_2015). This complex allele has also been reported in individuals with various cancers, although these findings have not been ascertained in the context of this evaluation. These data indicate that the variant in its complex allele configuration is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the complex allele on protein function (example, Horibata_2015). The most pronounced variant effect abolishes the helicase, Nucleotide Excision Repair (NER) activity and the transcriptional activity of TFIIH. However, although individually, p.Leu461Val and p.Ala717Gly possessed full NER activity (comparable to p.WT), the combined mutant p.[Leu461Val; Ala717Gly] possessed only partial NER activity. Due to the data presented as immunoprecipitation data on blots, an exact residual activity for the combined mutant cannot be ascertained from this report. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, as a surrogate representation of its complex allele configuration, this variant was classified as pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2022 | The c.2150C>G (p.A717G) alteration is located in coding exon 22 of the ERCC2 gene. This alteration results from a C to G substitution at nucleotide position 2150, causing the alanine (A) at amino acid position 717 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.03% (87/282626) total alleles studied. The highest observed frequency was 0.22% (23/10368) of Ashkenazi Jewish alleles. This mutation has been reported in conjunction with additional ERCC2 alterations in individuals with xeroderma pigmentosum and trichothiodystrophy (Takayama, 1995; Takayama, 1997; Fujimoto, 2005; Orioli, 2013; Zhou, 2013; Fassihi, 2016). Fibroblast cell lines derived from individuals with this mutation demonstrated aberrant splicing, expected to result in an in-frame deletion of 15 amino acids (V716_R730del) (Takayama, 1995; Horibata, 2015). Additional functional assays showed that XPD protein with the V716_R730 deletion is defective in nucleotide excision repair activity and could not form the TFIIH complex (Horibata, 2015). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
ERCC2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 09, 2019 | The ERCC2 c.2150C>G (p.Ala717Gly) variant creates a new splice donor site which results in altered splicing leading to a 15 amino acid deletion (p.Val716_Arg730del) (Takayama et al. 1995; Horibata et al. 2015). The p.Val716_Arg730del variant is described in at least six studies, in which it is always found in cis with a missense variant, c.1381C>G (p.Leu461Val), to give the complex allele: [c.1381C>G (p.Leu461Val); c.2150C>G (p.Val716_Arg730del)] (Takayama et al. 1995; Takayama et al. 1997; Moslehi et al. 2012; Orioli et al. 2013; Zhou et al. 2013; Horibata et al. 2015). The complex allele (p.Leu461Val; p.Val716_Arg730del) has been reported in a compound heterozygous state with another missense variant in a total of 16 individuals with either xeroderma pigmentosum (XP) or trichothiodystrophy. Orioli et al. (2013) report the (p.Leu461Val; p.Val716_Arg730del) allele in a compound heterozygous state with a missense variant in a patient with a severe XP phenotype. The patient had 48% of normal transcription factor TFIIH levels in fibroblasts and 10% of typical UV-induced DNA repair synthesis ability. Horibata et al. (2015) performed functional studies demonstrating that the (p.Leu461Val; p.Val716_Arg730del) allele was functionally null in nucleotide excision repair and not able to form the TFIIH complex. The p.Ala717Gly and p.Leu461Val variants in isolation performed similarly to wild type in nucleotide excision repair and were able to fully or partly form the TFIIH complex and rescue the UV hypersensitivity. Zhou et al. (2013) also showed that the (p.Leu461Val; p.Val716_Arg730del) allele exhibited decreased DNA repair. The p.Ala717Gly variant is reported at a frequency of 0.0005124 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the (p.Leu461Val; p.Val716_Arg730del) allele is classified as pathogenic for ERCC2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Cerebrooculofacioskeletal syndrome 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Trichothiodystrophy 1, photosensitive Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 27, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;.
REVEL
Uncertain
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
B;B;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at