chr19-45352801-C-G

Variant names:

• chr19-45352801-C-G
• rs376556895
• NM_000400.4:c.1847G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM5 PP3_Strong PP5_Very_Strong

The NM_000400.4(ERCC2):​c.1847G>C​(p.Arg616Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,613,336 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: "SCV000413569: Taylor et al. (1997) demonstrated that the p.Arg616Pro variant was unable to rescue lethality in a yeast complementation assay. When compared to control cell lines exposed to UV, fibroblasts from individuals carrying the p.Arg616Pro variant showed greater levels of apoptosis (Quielle et al. 2001) and reduced nucleotide excision repair capacity (Shafer et al. 2013), and the variant was noted to completely abolish basal transcription (Dubaele et al. 2003).; SCV000577052: Published functional studies on the yeast Rad15 gene, which is homologous to the human ERCC2 gene, demonstrate that the yeast R616P homologous variant is a functional null allele (PMID:9238033);; SCV001578448: Experimental studies have shown that this missense change affects ERCC2 function (PMID:9238033, 12820975).; SCV001365778: In vitro functional studies support an impact on protein function (Taylor 1997, Queille 2001, Dubaele 2003).; SCV001370738: Experimental studies have shown that the variant completely abolished basal transcription, failed to restore viability, and abolished more than 80% of excision repair activity (Dubaele_2003, Taylor_1997, Broughton_1994).; SCV003749556: In vitro studies of the homolog rad15 suggests this mutation is a null allele when it was observed that this mutation could not restore cell viability when compound heterozygous with a deletion mutation (Taylor, 1997).; SCV006324584: Functional studies have shown that this variant decreases repair activity (PMID:9238033, 23800062) (PS3).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R616Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.14
• Publications: 39 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: SCV000413569: Taylor et al. (1997) demonstrated that the p.Arg616Pro variant was unable to rescue lethality in a yeast complementation assay. When compared to control cell lines exposed to UV, fibroblasts from individuals carrying the p.Arg616Pro variant showed greater levels of apoptosis (Quielle et al. 2001) and reduced nucleotide excision repair capacity (Shafer et al. 2013), and the variant was noted to completely abolish basal transcription (Dubaele et al. 2003).; SCV000577052: Published functional studies on the yeast Rad15 gene, which is homologous to the human ERCC2 gene, demonstrate that the yeast R616P homologous variant is a functional null allele (PMID: 9238033);; SCV001578448: Experimental studies have shown that this missense change affects ERCC2 function (PMID: 9238033, 12820975).; SCV001365778: In vitro functional studies support an impact on protein function (Taylor 1997, Queille 2001, Dubaele 2003).; SCV001370738: Experimental studies have shown that the variant completely abolished basal transcription, failed to restore viability, and abolished more than 80% of excision repair activity (Dubaele_2003, Taylor_1997, Broughton_1994).; SCV003749556: In vitro studies of the homolog rad15 suggests this mutation is a null allele when it was observed that this mutation could not restore cell viability when compound heterozygous with a deletion mutation (Taylor, 1997).; SCV006324584: Functional studies have shown that this variant decreases repair activity (PMID: 9238033, 23800062) (PS3).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45352801-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 997520.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 19-45352801-C-G is Pathogenic according to our data. Variant chr19-45352801-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 329508.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.1847G>C	p.Arg616Pro	missense	Exon 20 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1775G>C	p.Arg592Pro	missense	Exon 20 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.1769G>C	p.Arg590Pro	missense	Exon 19 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.1847G>C	p.Arg616Pro	missense	Exon 20 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1847G>C	p.Arg616Pro	missense	Exon 20 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1775G>C	p.Arg592Pro	missense	Exon 19 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151734 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000728

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: 0.000265

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 250892 AF XY: 0.000125

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000297 AC: 434 AN: 1461602 Hom.: 0 Cov.: 37 AF XY: 0.000268 AC XY: 195 AN XY: 727080

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111860

Other (OTH) AF: 0.000298 AC: 18 AN: 60374

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151734 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74092

African (AFR) AF: 0.0000728 AC: 3 AN: 41228

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67932

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Xeroderma pigmentosum (3)
1	-	-	Cerebrooculofacioskeletal syndrome 2 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Xeroderma pigmentosum, group D (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	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.99
MPC		0.96
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		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: rs376556895; hg19: chr19-45856059; COSMIC: COSV67268805; COSMIC: COSV67268805;