rs3793784

Variant names:

Variant summary

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

The NM_001277059.2(ERCC6):c.-76C>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 0.299 in 152,182 control chromosomes in the GnomAD database, including 8,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 8399 hom., cov: 32)

Exomes 𝑓: 0.36 ( 11 hom. )

Consequence

ERCC6
NM_001277059.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.02

Publications

28 publications found

Variant links:

Genes affected

ERCC6 (HGNC:3438): (ERCC excision repair 6, chromatin remodeling factor) This gene encodes a DNA-binding protein that is important in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites. Mutations in this gene are associated with Cockayne syndrome type B and cerebrooculofacioskeletal syndrome 1. Alternative splicing occurs between a splice site from exon 5 of this gene to the 3' splice site upstream of the open reading frame (ORF) of the adjacent gene, piggyback-derived-3 (GeneID:267004), which activates the alternative polyadenylation site downstream of the piggyback-derived-3 ORF. The resulting transcripts encode a fusion protein that shares sequence with the product of each individual gene. [provided by RefSeq, Mar 2016]

ERCC6 Gene-Disease associations (from GenCC):

Cockayne spectrum with or without cerebrooculofacioskeletal syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Cockayne syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
UV-sensitive syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
UV-sensitive syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
premature ovarian failure 11
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ERCC6 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 10-49539493-G-C is Benign according to our data. Variant chr10-49539493-G-C is described in ClinVar as Benign. ClinVar VariationId is 1709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_001277059.2 link	c.-76C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6		NP_001263988.1
ERCC6	NM_001277059.2 link	c.-76C>G		5_prime_UTR_variant	Exon 1 of 6		NP_001263988.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
ERCC6	ENST00000515869.1 link	c.-76C>G	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	2	ENSP00000423550.1
ERCC6	ENST00000462247.1 link	c.-76C>G	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	3	ENSP00000422827.1
ERCC6	ENST00000515869.1 link	c.-76C>G	5_prime_UTR_variant	Exon 1 of 6	2	ENSP00000423550.1
ERCC6	ENST00000462247.1 link	c.-76C>G	5_prime_UTR_variant	Exon 1 of 3	3	ENSP00000422827.1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45505

AN:

151916

Hom.:

8408

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0793

Gnomad AMI

AF:

0.517

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.385

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.320

GnomAD4 exome

AF:

0.358

AC:

AN:

148

Hom.:

Cov.:

AF XY:

0.349

AC XY:

AN XY:

106

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.429

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.367

AC:

AN:

120

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.299

AC:

45479

AN:

152034

Hom.:

8399

Cov.:

AF XY:

0.297

AC XY:

22064

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0790

AC:

3278

AN:

41494

American (AMR)

AF:

0.305

AC:

4667

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1113

AN:

3470

East Asian (EAS)

AF:

0.318

AC:

1638

AN:

5146

South Asian (SAS)

AF:

0.262

AC:

1261

AN:

4822

European-Finnish (FIN)

AF:

0.385

AC:

4069

AN:

10558

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.415

AC:

28205

AN:

67942

Other (OTH)

AF:

0.318

AC:

672

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1514

3028

4541

6055

7569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.346

Hom.:

1371

Bravo

AF:

0.285

Asia WGS

AF:

0.276

AC:

964

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

LUNG CANCER, SUSCEPTIBILITY TO

Other:1

Jan 01, 2008

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Age related macular degeneration 5

Other:1

Dec 08, 2016

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.6

(source)

DANN

Benign

0.57

PhyloP100

2.0

PromoterAI

0.0020

Neutral

(source)

Splicing

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