19-45364001-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000400.4(ERCC2):​c.934G>A​(p.Asp312Asn) variant causes a missense change. The variant allele was found at a frequency of 0.319 in 1,543,626 control chromosomes in the GnomAD database, including 83,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D312G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (6406 hom., cov: 33)
  • Exomes 𝑓: 0.33 (77067 hom.)
• Consequence: ERCC2 NM_000400.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O: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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015462935).
• BP6: Variant 19-45364001-C-T is Benign according to our data. Variant chr19-45364001-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

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>A	p.Asp312Asn	missense	Exon 10 of 23	NP_000391.1
	ERCC2	NM_001440355.1		c.862G>A	p.Asp288Asn	missense	Exon 10 of 23	NP_001427284.1
	ERCC2	NM_001440356.1		c.856G>A	p.Asp286Asn	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>A	p.Asp312Asn	missense	Exon 10 of 23	ENSP00000375809.4
	ERCC2	ENST00000391944.8	TSL:1	c.934G>A	p.Asp312Asn	missense	Exon 10 of 22	ENSP00000375808.4
	ERCC2	ENST00000391941.6	TSL:1	c.862G>A	p.Asp288Asn	missense	Exon 9 of 21	ENSP00000375805.2

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40248 AN: 152048 Hom.: 6409 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.290 AC: 41034 AN: 141480 AF XY: 0.301

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.363

Gnomad EAS exome AF: 0.0431

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.325 AC: 452603 AN: 1391460 Hom.: 77067 Cov.: 54 AF XY: 0.328 AC XY: 225055 AN XY: 686616

African (AFR) AF: 0.102 AC: 3218 AN: 31672

American (AMR) AF: 0.198 AC: 7108 AN: 35820

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 8935 AN: 25106

East Asian (EAS) AF: 0.0399 AC: 1432 AN: 35924

South Asian (SAS) AF: 0.350 AC: 27909 AN: 79628

European-Finnish (FIN) AF: 0.366 AC: 15047 AN: 41080

Middle Eastern (MID) AF: 0.386 AC: 2093 AN: 5426

European-Non Finnish (NFE) AF: 0.342 AC: 369379 AN: 1078936

Other (OTH) AF: 0.302 AC: 17482 AN: 57868

GnomAD4 genome AF: 0.264 AC: 40240 AN: 152166 Hom.: 6406 Cov.: 33 AF XY: 0.264 AC XY: 19676 AN XY: 74394

African (AFR) AF: 0.113 AC: 4691 AN: 41536

American (AMR) AF: 0.229 AC: 3503 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1220 AN: 3470

East Asian (EAS) AF: 0.0467 AC: 242 AN: 5178

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4828

European-Finnish (FIN) AF: 0.370 AC: 3915 AN: 10588

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23876 AN: 67960

Other (OTH) AF: 0.269 AC: 568 AN: 2112

Alfa AF: 0.308 Hom.: 5827

Bravo AF: 0.243

TwinsUK AF: 0.361 AC: 1338

ALSPAC AF: 0.339 AC: 1307

ESP6500AA AF: 0.0976 AC: 387

ESP6500EA AF: 0.317 AC: 2507

ExAC AF: 0.213 AC: 21786

Asia WGS AF: 0.168 AC: 589 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	4	Xeroderma pigmentosum, group D (4)
-	-	3	not provided (3)
-	-	1	Cerebrooculofacioskeletal syndrome 2 (1)
-	-	1	Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Polyphen		0.053	B
Vest4		0.23
MPC		0.28
ClinPred		0.018	T
GERP RS		5.2
Varity_R		0.59
gMVP		0.66
Mutation Taster		=89/11	polymorphism (auto)

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; COSMIC: COSV55538614; COSMIC: COSV55538614;