rs144564120

Variant names:

• chr19-45352249-G-C
• rs144564120
• NM_000400.4:c.2150C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-45352249-G-C
• chr19-45352249-G-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP3_Moderate PP5_Very_Strong

The NM_000400.4(ERCC2):​c.2150C>G​(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 (★★). ClinVar reports functional evidence for this variant: "SCV000322086: RNA studies suggest that the c.2150C>G variant creates a cryptic splice donor site upstream of the natural splice site, leading to an in-frame deletion of 15 amino acids (PMID:7585650)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A717A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1 O:1
• Conservation: PhyloP100: 9.00
• Publications: 20 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322086: RNA studies suggest that the c.2150C>G variant creates a cryptic splice donor site upstream of the natural splice site, leading to an in-frame deletion of 15 amino acids (PMID: 7585650); Published functional studies also suggest that A717G was similar to wildtype in UV survival assays and TFIIH binding, but when expressed in cis with L461V, cells were more sensitive at high doses of UV; however, the significance of this result is unclear due to a lack known controls (PMID: 25716912);; SCV002228642: Experimental studies have shown that this missense change affects ERCC2 function (PMID: 7585650, 15982307, 25716912).; SCV000914845: 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. Zhou et al. (2013) also showed that the (p.Leu461Val; p.Val716_Arg730del) allele exhibited decreased DNA repair.; SCV004812413: "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; SCV003654229: 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).; SCV003800757: "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. Horibata_2015"; SCV003800758: 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.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000400.4
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 134102.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.2150C>G	p.Ala717Gly	missense	Exon 22 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.2078C>G	p.Ala693Gly	missense	Exon 22 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.2072C>G	p.Ala691Gly	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.2150C>G	p.Ala717Gly	missense	Exon 22 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.2150C>G	p.Ala717Gly	missense	Exon 22 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.2078C>G	p.Ala693Gly	missense	Exon 21 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251244 AF XY: 0.000331

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000465 AC: 679 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.000451 AC XY: 328 AN XY: 727184

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000224 AC: 10 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000506 AC: 563 AN: 1111982

Other (OTH) AF: 0.000530 AC: 32 AN: 60388

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74334

African (AFR) AF: 0.000145 AC: 6 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Xeroderma pigmentosum, group D (4)
3	-	-	not provided (3)
2	-	-	Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive (2)
1	-	-	ERCC2-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified (1)
1	-	-	Trichothiodystrophy 1, photosensitive (1)
1	-	-	Xeroderma pigmentosum (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.038	D
Polyphen		0.015	B
Vest4		0.62
MVP		0.89
MPC		0.30
ClinPred		0.64	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.43
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: 5

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

Other links and lift over

dbSNP: rs144564120; hg19: chr19-45855507; COSMIC: COSV109439200;