Genetic Variant ERCC2:p.Leu461Val (chr19-45357368-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_000400.4(ERCC2):c.1381C>G(p.Leu461Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,613,648 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L461P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 9 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:4O:1

Conservation

PhyloP100: 8.35

Publications

27 publications found

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 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

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-45357368-G-C is Benign according to our data. Variant chr19-45357368-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16779.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000492 (75/152356) while in subpopulation SAS AF = 0.00705 (34/4826). AF 95% confidence interval is 0.00518. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC2	NM_000400.4	MANE Select	c.1381C>G	p.Leu461Val	missense	Exon 15 of 23	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.1309C>G	p.Leu437Val	missense	Exon 15 of 23	NP_001427284.1
ERCC2	NM_001440356.1		c.1303C>G	p.Leu435Val	missense	Exon 14 of 22	NP_001427285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.1381C>G	p.Leu461Val	missense	Exon 15 of 23	ENSP00000375809.4	P18074-1
ERCC2	ENST00000391944.8	TSL:1	c.1381C>G	p.Leu461Val	missense	Exon 15 of 22	ENSP00000375808.4	E7EVE9
ERCC2	ENST00000391941.6	TSL:1	c.1309C>G	p.Leu437Val	missense	Exon 14 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00120

AC:

302

AN:

251138

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000895

AC:

1308

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

809

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33464

American (AMR)

AF:

0.000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00696

AC:

600

AN:

86234

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000510

AC:

567

AN:

1111494

Other (OTH)

AF:

0.000944

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000492

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41594

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00705

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000411

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000625

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Xeroderma pigmentosum, group D (5)

not provided (3)

Inborn genetic diseases (1)

not specified (2)

Trichothiodystrophy 1, photosensitive (1)

Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.4

PhyloP100

8.3

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.98

Vest4

0.96

MVP

0.87

MPC

0.62

ClinPred

0.16

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.79

Mutation Taster

=21/79

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.75

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over