19-45364001-C-T

Variant summary

Our verdict is Benign. Variant got -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. D312E) 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:13 O:1
• Conservation: PhyloP100: 4.64

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 134117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45364001-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC2	NM_000400.4	c.934G>A	p.Asp312Asn	missense_variant	10/23	ENST00000391945.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10	c.934G>A	p.Asp312Asn	missense_variant	10/23	1	NM_000400.4	P1

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

GnomAD3 exomes AF: 0.290 AC: 41034 AN: 141480 Hom.: 6833 AF XY: 0.301 AC XY: 23207 AN XY: 77124

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 SAS exome AF: 0.350

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

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.356

Gnomad4 EAS exome AF: 0.0399

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.342

Gnomad4 OTH exome AF: 0.302

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

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.0467

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.269

Alfa AF: 0.315 Hom.: 4031

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

Significance: Benign/Likely benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with cancer risk -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Xeroderma pigmentosum, group D Benign:4

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	This variant is associated with the following publications: (PMID: 27306318, 24841663, 25916209, 24101192, 24933002, 23973729, 29989875, 27153395, 24868140, 11606376, 19041121, 24728327, 21245954, 19242824, 21643959, 19669592, 19055600, 18641418, 22184993, 14630517, 20070155, 19706757) -

Cerebrooculofacioskeletal syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Trichothiodystrophy 1, photosensitive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;.
Eigen	Benign	0.066
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	2.2e-8	P;P;P;P;P
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;D;.;D;.
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;.;T;.
Sift4G	Benign	0.14	T;T;T;T;.
Polyphen		0.053	B;B;.;.;.
Vest4		0.23
MPC		0.28
ClinPred		0.018	T
GERP RS		5.2
Varity_R		0.59
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs1799793; hg19: chr19-45867259; COSMIC: COSV55538614; COSMIC: COSV55538614;