chr19-45352235-G-A

Variant names:

• chr19-45352235-G-A
• rs121913026
• NM_000400.4:c.2164C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000400.4(ERCC2):​c.2164C>T​(p.Arg722Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005417589: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R722L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 0.263
• Publications: 64 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, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005417589: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000322047: Published functional studies demonstrate that R722W disrupts RARB2 mRNA synthesis by deregulating several transcriptional steps and destabilizes the architecture of the evolutionarily conserved general transcription factor IIH (TFIIH) (Singh et al., 2015);; SCV001370695: At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.Arg722Trp affected normal activity (e.g. Singh_2015).; SCV001653116: "In vitro functional studies support an impact on protein function (Pehlivan 2012 PMID:23039039, Singh 2015 PMID:25620205)."; SCV001443751: Functional studies using patient fibroblast cell lines show that this variant impedes the recruitment of transcription repair factor TFIIH to sites of DNA damage, at least in part by weakening the interaction of ERCC2 with the GTF2H2 subunit (PMID: 18817897, 25620205). Another study using patient fibroblast cells shows that this variant results in a drastic reduction in the expression of collagen type VI alpha1 subunit, an important component of soft connective tissues, due to impaired TFIIH function (PMID: 23221806).; SCV004120072: Functional studies of cells isolated from patients with this variant showed high sensitivity to UV light and decreased DNA repair (Takayama et al. 1996. PubMed ID: 8571952; Nishiwaki et al. 2008. PubMed ID: 18817897).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000400.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 19-45352235-G-A is Pathogenic according to our data. Variant chr19-45352235-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.2164C>T	p.Arg722Trp	missense	Exon 22 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.2092C>T	p.Arg698Trp	missense	Exon 22 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.2086C>T	p.Arg696Trp	missense	Exon 21 of 22	NP_001427285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2164C>T	p.Arg722Trp	missense	Exon 22 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.2164C>T	p.Arg722Trp	missense	Exon 22 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.2092C>T	p.Arg698Trp	missense	Exon 21 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251074 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461726 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111974

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.000193 AC: 8 AN: 41440

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000629 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Cerebrooculofacioskeletal syndrome 2 (3)
2	-	-	ERCC2-related disorder (2)
2	-	-	Trichothiodystrophy 1, photosensitive (2)
1	-	-	Hypotrichosis simplex (1)
1	-	-	Trichothiodystrophy (1)
1	-	-	Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.023
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.26
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.94
MPC		0.81
ClinPred		0.96	D
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.71
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121913026; hg19: chr19-45855493;