19-45364001-C-A

Variant names:

• chr19-45364001-C-A
• rs1799793
• NM_000400.4:c.934G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000400.4(ERCC2):​c.934G>T​(p.Asp312Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,391,598 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D312N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64
• Publications: 625 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, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• xeroderma pigmentosum group D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	NM_000400.4	MANE Select	c.934G>T	p.Asp312Tyr	missense	Exon 10 of 23	NP_000391.1
	ERCC2	NM_001440355.1		c.862G>T	p.Asp288Tyr	missense	Exon 10 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.856G>T	p.Asp286Tyr	missense	Exon 9 of 22	NP_001427285.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.934G>T	p.Asp312Tyr	missense	Exon 10 of 23	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.934G>T	p.Asp312Tyr	missense	Exon 10 of 22	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.862G>T	p.Asp288Tyr	missense	Exon 9 of 21	ENSP00000375805.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000707 AC: 1 AN: 141480 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391598 Hom.: 0 Cov.: 54 AF XY: 0.00000291 AC XY: 2 AN XY: 686696

African (AFR) AF: 0.00 AC: 0 AN: 31672

American (AMR) AF: 0.0000279 AC: 1 AN: 35820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 35926

South Asian (SAS) AF: 0.00 AC: 0 AN: 79630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079022

Other (OTH) AF: 0.00 AC: 0 AN: 57874

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.64	P
Vest4		0.72
MutPred		0.50		Loss of disorder (P = 0.0494)
MVP		0.85
MPC		0.87
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.84
Mutation Taster		=22/78	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: rs1799793; hg19: chr19-45867259;