NM_000400.4:c.1802G>C

Variant names:

• chr19-45353112-C-G
• rs140522180
• NM_000400.4:c.1802G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000400.4(ERCC2):​c.1802G>C​(p.Arg601Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R601W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.56
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45353112-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2573404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

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.1802G>C	p.Arg601Pro	missense	Exon 19 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.1730G>C	p.Arg577Pro	missense	Exon 19 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.1724G>C	p.Arg575Pro	missense	Exon 18 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.1802G>C	p.Arg601Pro	missense	Exon 19 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.1802G>C	p.Arg601Pro	missense	Exon 19 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.1730G>C	p.Arg577Pro	missense	Exon 18 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461288 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726950

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60344

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.80		Loss of methylation at R601 (P = 0.0384)
MVP		0.90
MPC		0.97
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.94
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs140522180; hg19: chr19-45856370; COSMIC: COSV107491761; COSMIC: COSV107491761;