19-45351661-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000400.4(ERCC2):c.2251A>C(p.Lys751Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,613,486 control chromosomes in the GnomAD database, including 103,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K751K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 8237 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95730 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:3

Conservation

PhyloP100: 1.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044302046).

BP6

Variant 19-45351661-T-G is Benign according to our data. Variant chr19-45351661-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45351661-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC2	NM_000400.4 linkuse as main transcript	c.2251A>C	p.Lys751Gln	missense_variant	23/23	ENST00000391945.10
ERCC2	XM_011526611.3 linkuse as main transcript	c.2173A>C	p.Lys725Gln	missense_variant	22/22
ERCC2	XR_001753633.3 linkuse as main transcript	n.2284A>C		non_coding_transcript_exon_variant	23/24
ERCC2	XR_007066680.1 linkuse as main transcript	n.2206A>C		non_coding_transcript_exon_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC2	ENST00000391945.10 linkuse as main transcript	c.2251A>C	p.Lys751Gln	missense_variant	23/23	1	NM_000400.4	P1	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.316

AC:

47995

AN:

151946

Hom.:

8232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.0729

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.418

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.374

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.325

AC:

81291

AN:

250340

Hom.:

14643

AF XY:

0.336

AC XY:

45527

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.422

Gnomad EAS exome

AF:

0.0755

Gnomad SAS exome

AF:

0.371

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.355

AC:

519083

AN:

1461422

Hom.:

95730

Cov.:

AF XY:

0.357

AC XY:

259873

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.224

Gnomad4 AMR exome

AF:

0.206

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.0556

Gnomad4 SAS exome

AF:

0.376

Gnomad4 FIN exome

AF:

0.417

Gnomad4 NFE exome

AF:

0.370

Gnomad4 OTH exome

AF:

0.343

GnomAD4 genome

AF:

0.316

AC:

48019

AN:

152064

Hom.:

8237

Cov.:

AF XY:

0.316

AC XY:

23521

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.253

Gnomad4 ASJ

AF:

0.399

Gnomad4 EAS

AF:

0.0725

Gnomad4 SAS

AF:

0.363

Gnomad4 FIN

AF:

0.418

Gnomad4 NFE

AF:

0.374

Gnomad4 OTH

AF:

0.320

Alfa

AF:

0.357

Hom.:

21112

Bravo

AF:

0.295

TwinsUK

AF:

0.385

AC:

1426

ALSPAC

AF:

0.363

AC:

1399

ESP6500AA

AF:

0.235

AC:

1037

ESP6500EA

AF:

0.372

AC:

3203

ExAC

AF:

0.330

AC:

40010

Asia WGS

AF:

0.185

AC:

649

AN:

3478

EpiCase

AF:

0.382

EpiControl

AF:

0.380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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 reduced cancer risk -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Xeroderma pigmentosum, group D

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2019	This variant is associated with the following publications: (PMID: 24645270, 17630853, 27306318, 24325908, 26482462, 26001739, 25873778, 24101192, 25113251, 24362511, 25023406, 24787743, 22183071, 24892639, 29723101, 29989875, 24763305, 26354780, 24556168, 26086338, 24486506, 24368330, 9950243, 18230301, 19051060, 24728327, 20514470, 22844363, 19027756, 21617750, 21667112, 21559836, 19669592, 22525558, 19116388, 18534129, 21390047, 19615095, 20375340, 19055600, 18641418, 22179996, 22184993, 20627704, 14630517, 10753184, 19919686, 22496165, 19707883, 22797977, 20204500, 27153395) -

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

- -

Bone osteosarcoma

Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Non-small cell lung carcinoma

Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

Cadd

Benign

Dann

Benign

0.63

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.20

Sift

Benign

0.58

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;B

Vest4

0.073

MPC

0.22

ClinPred

0.0018

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.085

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over