Genetic Variant ERCC2:p.Ala734Ala (chr19-45352197-C-T) – 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 ENST00000391944.8(ERCC2):c.2202G>A(p.Ala734Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,114 control chromosomes in the GnomAD database, including 105 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. A734A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 88 hom. )

Consequence

ERCC2
ENST00000391944.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.82

Publications

3 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=-0.82).

BP6

Variant 19-45352197-C-T is Benign according to our data. Variant chr19-45352197-C-T is described in ClinVar as Benign. ClinVar VariationId is 256019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000391944.8. 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.2190+12G>A	intron	N/A	NP_000391.1	P18074-1
ERCC2	NM_001440355.1		c.2118+12G>A	intron	N/A	NP_001427284.1
ERCC2	NM_001440356.1		c.2112+12G>A	intron	N/A	NP_001427285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC2	ENST00000391944.8	TSL:1	c.2202G>A	p.Ala734Ala	synonymous	Exon 22 of 22	ENSP00000375808.4	E7EVE9
ERCC2	ENST00000391945.10	TSL:1 MANE Select	c.2190+12G>A		intron	N/A	ENSP00000375809.4	P18074-1
ERCC2	ENST00000891927.1		c.2286+12G>A		intron	N/A	ENSP00000561986.1

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

632

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0597

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00520

AC:

1298

AN:

249692

AF XY:

0.00462

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.000638

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0594

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00220

AC:

3221

AN:

1460894

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1522

AN XY:

726756

show subpopulations

African (AFR)

AF:

0.00669

AC:

224

AN:

33460

American (AMR)

AF:

0.000649

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26126

East Asian (EAS)

AF:

0.0549

AC:

2179

AN:

39688

South Asian (SAS)

AF:

0.00183

AC:

158

AN:

86196

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.00130

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.000186

AC:

207

AN:

1111792

Other (OTH)

AF:

0.00686

AC:

414

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

198

396

593

791

989

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00416

AC:

633

AN:

152220

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00643

AC:

267

AN:

41536

American (AMR)

AF:

0.00190

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0594

AC:

307

AN:

5168

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68006

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00476

Asia WGS

AF:

0.0350

AC:

121

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Xeroderma pigmentosum, group D (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.1

(source)

DANN

Benign

0.71

PhyloP100

-2.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over