chr19-45352842-G-A

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.1832-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,609,886 control chromosomes in the GnomAD database, including 2,855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 159 hom., cov: 31)

Exomes 𝑓: 0.058 ( 2696 hom. )

Consequence

ERCC2
NM_000400.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.211

Publications

8 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, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
xeroderma pigmentosum group D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), 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=-0.87).

BP6

Variant 19-45352842-G-A is Benign according to our data. Variant chr19-45352842-G-A is described in ClinVar as Benign. ClinVar VariationId is 1248418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4 link	c.1832-26C>T		intron_variant	Intron 19 of 22	ENST00000391945.10	NP_000391.1	P18074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.1832-26C>T		intron_variant	Intron 19 of 22	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.0443

AC:

6728

AN:

151894

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0288

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0444

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0601

Gnomad OTH

AF:

0.0480

GnomAD2 exomes

AF:

0.0467

AC:

11616

AN:

248820

AF XY:

0.0481

show subpopulations

Gnomad AFR exome

AF:

0.0311

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0499

Gnomad NFE exome

AF:

0.0620

Gnomad OTH exome

AF:

0.0548

GnomAD4 exome

AF:

0.0579

AC:

84444

AN:

1457874

Hom.:

2696

Cov.:

AF XY:

0.0578

AC XY:

41918

AN XY:

725458

show subpopulations

African (AFR)

AF:

0.0288

AC:

963

AN:

33412

American (AMR)

AF:

0.0238

AC:

1063

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0509

AC:

1328

AN:

26116

East Asian (EAS)

AF:

0.000176

AC:

AN:

39666

South Asian (SAS)

AF:

0.0498

AC:

4288

AN:

86170

European-Finnish (FIN)

AF:

0.0501

AC:

2650

AN:

52858

Middle Eastern (MID)

AF:

0.0458

AC:

263

AN:

5748

European-Non Finnish (NFE)

AF:

0.0636

AC:

70510

AN:

1108990

Other (OTH)

AF:

0.0560

AC:

3372

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

4850

9700

14551

19401

24251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2612

5224

7836

10448

13060

<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:

0.0443

AC:

6738

AN:

152012

Hom.:

159

Cov.:

AF XY:

0.0431

AC XY:

3206

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0299

AC:

1240

AN:

41448

American (AMR)

AF:

0.0288

AC:

440

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

148

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.0465

AC:

224

AN:

4818

European-Finnish (FIN)

AF:

0.0444

AC:

471

AN:

10608

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0601

AC:

4081

AN:

67938

Other (OTH)

AF:

0.0475

AC:

100

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

324

648

971

1295

1619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0460

Hom.:

Bravo

AF:

0.0430

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.64

(source)

DANN

Benign

0.76

PhyloP100

0.21

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over