rs3810366

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The ENST00000391941.6(ERCC2):c.-519C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 834,764 control chromosomes in the GnomAD database, including 98,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 25874 hom., cov: 31)

Exomes 𝑓: 0.46 ( 73002 hom. )

Consequence

ERCC2
ENST00000391941.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0260

Publications

36 publications found

Variant links:

COSMIC-nc: COSV55543445

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: Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
xeroderma pigmentosum group D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript ENST00000391941.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.75).

BP6

Variant 19-45370684-G-C is Benign according to our data. Variant chr19-45370684-G-C is described in ClinVar as Benign. ClinVar VariationId is 1221224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000391941.6. 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.-144C>G	upstream_gene	N/A	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.-281C>G	upstream_gene	N/A	NP_001427284.1
ERCC2	NM_001440356.1		c.-144C>G	upstream_gene	N/A	NP_001427285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERCC2	ENST00000391941.6	TSL:1	c.-519C>G	5_prime_UTR_premature_start_codon_gain	Exon 1 of 21	ENSP00000375805.2	A8MX75
ERCC2	ENST00000391941.6	TSL:1	c.-519C>G	5_prime_UTR	Exon 1 of 21	ENSP00000375805.2	A8MX75
ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.-144C>G	upstream_gene	N/A	ENSP00000375809.4	P18074-1

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

84183

AN:

151986

Hom.:

25824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.845

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.467

Gnomad ASJ

AF:

0.473

Gnomad EAS

AF:

0.465

Gnomad SAS

AF:

0.472

Gnomad FIN

AF:

0.424

Gnomad MID

AF:

0.544

Gnomad NFE

AF:

0.435

Gnomad OTH

AF:

0.518

GnomAD4 exome

AF:

0.457

AC:

311674

AN:

682660

Hom.:

73002

Cov.:

AF XY:

0.457

AC XY:

162929

AN XY:

356410

show subpopulations

African (AFR)

AF:

0.848

AC:

15246

AN:

17978

American (AMR)

AF:

0.469

AC:

15402

AN:

32872

Ashkenazi Jewish (ASJ)

AF:

0.479

AC:

9570

AN:

19980

East Asian (EAS)

AF:

0.457

AC:

14576

AN:

31904

South Asian (SAS)

AF:

0.493

AC:

31735

AN:

64370

European-Finnish (FIN)

AF:

0.425

AC:

14013

AN:

32984

Middle Eastern (MID)

AF:

0.484

AC:

1991

AN:

4112

European-Non Finnish (NFE)

AF:

0.434

AC:

192791

AN:

444232

Other (OTH)

AF:

0.478

AC:

16350

AN:

34228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

8064

16129

24193

32258

40322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3372

6744

10116

13488

16860

<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:

0.554

AC:

84289

AN:

152104

Hom.:

25874

Cov.:

AF XY:

0.550

AC XY:

40858

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.845

AC:

35088

AN:

41512

American (AMR)

AF:

0.468

AC:

7140

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.473

AC:

1643

AN:

3472

East Asian (EAS)

AF:

0.465

AC:

2404

AN:

5168

South Asian (SAS)

AF:

0.471

AC:

2271

AN:

4818

European-Finnish (FIN)

AF:

0.424

AC:

4485

AN:

10590

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29523

AN:

67952

Other (OTH)

AF:

0.519

AC:

1098

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1690

3379

5069

6758

8448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.303

Hom.:

651

Bravo

AF:

0.574

Asia WGS

AF:

0.497

AC:

1731

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.8

(source)

DANN

Benign

0.39

PhyloP100

0.026

PromoterAI

-0.028

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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