rs1799783

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000400.4(ERCC2):c.247-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,571,972 control chromosomes in the GnomAD database, including 253,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 32443 hom., cov: 32)

Exomes 𝑓: 0.56 ( 221266 hom. )

Consequence

ERCC2
NM_000400.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.77

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-45368778-C-T is Benign according to our data. Variant chr19-45368778-C-T is described in ClinVar as Benign. ClinVar VariationId is 256020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	Effect	Exon Rank	Protein	UniProt
ERCC2	NM_000400.4	MANE Select	c.247-35G>A	intron	N/A	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.175-35G>A	intron	N/A	NP_001427284.1
ERCC2	NM_001440356.1		c.169-35G>A	intron	N/A	NP_001427285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.247-35G>A	intron	N/A	ENSP00000375809.4	P18074-1
ERCC2	ENST00000391944.8	TSL:1	c.247-35G>A	intron	N/A	ENSP00000375808.4	E7EVE9
ERCC2	ENST00000391941.6	TSL:1	c.175-35G>A	intron	N/A	ENSP00000375805.2	A8MX75

Frequencies

GnomAD3 genomes

AF:

0.636

AC:

96627

AN:

151884

Hom.:

32391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.869

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.584

Gnomad EAS

AF:

0.500

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.589

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.546

Gnomad OTH

AF:

0.593

GnomAD2 exomes

AF:

0.575

AC:

129793

AN:

225820

AF XY:

0.572

show subpopulations

Gnomad AFR exome

AF:

0.875

Gnomad AMR exome

AF:

0.516

Gnomad ASJ exome

AF:

0.602

Gnomad EAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.591

Gnomad NFE exome

AF:

0.550

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.555

AC:

788211

AN:

1419970

Hom.:

221266

Cov.:

AF XY:

0.556

AC XY:

393502

AN XY:

707222

show subpopulations

African (AFR)

AF:

0.882

AC:

28719

AN:

32550

American (AMR)

AF:

0.512

AC:

21315

AN:

41642

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

15217

AN:

25718

East Asian (EAS)

AF:

0.494

AC:

19222

AN:

38942

South Asian (SAS)

AF:

0.600

AC:

50722

AN:

84468

European-Finnish (FIN)

AF:

0.589

AC:

30940

AN:

52558

Middle Eastern (MID)

AF:

0.593

AC:

3314

AN:

5584

European-Non Finnish (NFE)

AF:

0.542

AC:

585365

AN:

1079570

Other (OTH)

AF:

0.567

AC:

33397

AN:

58938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

19205

38411

57616

76822

96027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16542

33084

49626

66168

82710

<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:

0.636

AC:

96731

AN:

152002

Hom.:

32443

Cov.:

AF XY:

0.633

AC XY:

47048

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.869

AC:

36033

AN:

41478

American (AMR)

AF:

0.525

AC:

8008

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2028

AN:

3472

East Asian (EAS)

AF:

0.501

AC:

2581

AN:

5156

South Asian (SAS)

AF:

0.586

AC:

2817

AN:

4806

European-Finnish (FIN)

AF:

0.589

AC:

6226

AN:

10562

Middle Eastern (MID)

AF:

0.619

AC:

182

AN:

294

European-Non Finnish (NFE)

AF:

0.546

AC:

37103

AN:

67960

Other (OTH)

AF:

0.593

AC:

1250

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1644

3288

4933

6577

8221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

770

1540

2310

3080

3850

<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:

0.603

Hom.:

5388

Bravo

AF:

0.643

Asia WGS

AF:

0.563

AC:

1961

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Xeroderma pigmentosum, group D (2)

Cerebrooculofacioskeletal syndrome 2 (1)

not specified (1)

Trichothiodystrophy 1, photosensitive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.82

(source)

DANN

Benign

0.47

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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