rs376556895

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000400.4(ERCC2):c.1847G>C(p.Arg616Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,613,336 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R616Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

ERCC2
NM_000400.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 5.14

Publications

39 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: Pathogenic. The variant received 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-45352801-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 997520.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 19-45352801-C-G is Pathogenic according to our data. Variant chr19-45352801-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 329508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1847G>C	p.Arg616Pro	missense	Exon 20 of 23	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.1775G>C	p.Arg592Pro	missense	Exon 20 of 23	NP_001427284.1
ERCC2	NM_001440356.1		c.1769G>C	p.Arg590Pro	missense	Exon 19 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.1847G>C	p.Arg616Pro	missense	Exon 20 of 23	ENSP00000375809.4	P18074-1
ERCC2	ENST00000391944.8	TSL:1	c.1847G>C	p.Arg616Pro	missense	Exon 20 of 22	ENSP00000375808.4	E7EVE9
ERCC2	ENST00000391941.6	TSL:1	c.1775G>C	p.Arg592Pro	missense	Exon 19 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151734

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000151

AC:

AN:

250892

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000274

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000297

AC:

434

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

195

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000367

AC:

408

AN:

1111860

Other (OTH)

AF:

0.000298

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000145

AC:

AN:

151734

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.0000728

AC:

AN:

41228

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67932

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000227

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Xeroderma pigmentosum (3)

Cerebrooculofacioskeletal syndrome 2 (1)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Xeroderma pigmentosum, group D (1)

Xeroderma pigmentosum, group D;C1853102:Cerebrooculofacioskeletal syndrome 2;C1866504:Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

PhyloP100

5.1

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.99

MVP

0.99

MPC

0.96

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.97

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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