dbSNP rs238406: ERCC2:p.Arg156Arg (chr19-45365051-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000400.4(ERCC2):c.468A>C(p.Arg156Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,612,802 control chromosomes in the GnomAD database, including 265,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R156R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.64 ( 32867 hom., cov: 33)

Exomes 𝑓: 0.56 ( 232819 hom. )

Consequence

ERCC2
NM_000400.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.83

Publications

191 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 19-45365051-T-G is Benign according to our data. Variant chr19-45365051-T-G is described in ClinVar as Benign. ClinVar VariationId is 256021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.861 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC2	NM_000400.4	MANE Select	c.468A>C	p.Arg156Arg	synonymous	Exon 6 of 23	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.396A>C	p.Arg132Arg	synonymous	Exon 6 of 23	NP_001427284.1
ERCC2	NM_001440356.1		c.390A>C	p.Arg130Arg	synonymous	Exon 5 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.468A>C	p.Arg156Arg	synonymous	Exon 6 of 23	ENSP00000375809.4	P18074-1
ERCC2	ENST00000391944.8	TSL:1	c.468A>C	p.Arg156Arg	synonymous	Exon 6 of 22	ENSP00000375808.4	E7EVE9
ERCC2	ENST00000391941.6	TSL:1	c.396A>C	p.Arg132Arg	synonymous	Exon 5 of 21	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

97410

AN:

152066

Hom.:

32816

Cov.:

show subpopulations

Gnomad AFR

AF:

0.869

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.588

Gnomad EAS

AF:

0.497

Gnomad SAS

AF:

0.589

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.580

AC:

144875

AN:

249946

AF XY:

0.577

show subpopulations

Gnomad AFR exome

AF:

0.877

Gnomad AMR exome

AF:

0.517

Gnomad ASJ exome

AF:

0.605

Gnomad EAS exome

AF:

0.509

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.557

Gnomad OTH exome

AF:

0.561

GnomAD4 exome

AF:

0.562

AC:

820439

AN:

1460618

Hom.:

232819

Cov.:

AF XY:

0.563

AC XY:

409020

AN XY:

726670

show subpopulations

African (AFR)

AF:

0.882

AC:

29531

AN:

33470

American (AMR)

AF:

0.515

AC:

23008

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.596

AC:

15562

AN:

26132

East Asian (EAS)

AF:

0.490

AC:

19449

AN:

39684

South Asian (SAS)

AF:

0.603

AC:

52019

AN:

86226

European-Finnish (FIN)

AF:

0.593

AC:

31676

AN:

53382

Middle Eastern (MID)

AF:

0.597

AC:

3446

AN:

5768

European-Non Finnish (NFE)

AF:

0.550

AC:

611271

AN:

1110954

Other (OTH)

AF:

0.571

AC:

34477

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

19025

38049

57074

76098

95123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17298

34596

51894

69192

86490

<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:

0.641

AC:

97513

AN:

152184

Hom.:

32867

Cov.:

AF XY:

0.638

AC XY:

47443

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.869

AC:

36100

AN:

41552

American (AMR)

AF:

0.529

AC:

8094

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

2043

AN:

3472

East Asian (EAS)

AF:

0.497

AC:

2567

AN:

5164

South Asian (SAS)

AF:

0.589

AC:

2841

AN:

4822

European-Finnish (FIN)

AF:

0.594

AC:

6288

AN:

10590

Middle Eastern (MID)

AF:

0.619

AC:

182

AN:

294

European-Non Finnish (NFE)

AF:

0.553

AC:

37614

AN:

67968

Other (OTH)

AF:

0.599

AC:

1265

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1707

3414

5121

6828

8535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.576

Hom.:

50100

Bravo

AF:

0.647

Asia WGS

AF:

0.562

AC:

1958

AN:

3478

EpiCase

AF:

0.565

EpiControl

AF:

0.559

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Xeroderma pigmentosum, group D (3)

Cerebrooculofacioskeletal syndrome 2 (1)

Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

1.8

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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