NM_000400.4:c.679C>G

Variant names:

• chr19-45364463-G-C
• rs137910235
• NM_000400.4:c.679C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000400.4(ERCC2):​c.679C>G​(p.Arg227Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,714 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. R227C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 5 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

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.679C>G	p.Arg227Gly	missense	Exon 8 of 23	NP_000391.1	P18074-1
	ERCC2	NM_001440355.1		c.607C>G	p.Arg203Gly	missense	Exon 8 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.601C>G	p.Arg201Gly	missense	Exon 7 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.679C>G	p.Arg227Gly	missense	Exon 8 of 23	ENSP00000375809.4	P18074-1
	ERCC2	ENST00000391944.8	TSL:1	c.679C>G	p.Arg227Gly	missense	Exon 8 of 22	ENSP00000375808.4	E7EVE9
	ERCC2	ENST00000391941.6	TSL:1	c.607C>G	p.Arg203Gly	missense	Exon 7 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250582 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461714 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	M
PhyloP100		3.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		0.20	B
Vest4		0.36
MutPred		0.49		Loss of stability (P = 0.026)
MVP		0.81
MPC		0.58
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.36
gMVP		0.31
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137910235; hg19: chr19-45867721;