rs1198241866

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000124.4(ERCC6):c.1009A>T(p.Lys337*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K337K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ERCC6
NM_000124.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.49

Publications

4 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 links:

PGBD3 (HGNC:19400): (piggyBac transposable element derived 3) This gene is a member of a small family of genes derived from piggyBac transposable elements. The encoded protein contains a zinc-ribbon domain characteristic of transposon-derived proteins and may function as a regulator of transcription. Alternative splicing occurs between a splice site from exon 5 of the adjacent upstream gene 'excision repair cross-complementation group 6' (ERCC6, GeneID: 2074) and the 3' splice site upstream of the open reading frame (ORF) of this gene, 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. Pseudogenes for this gene are defined on chromosomes 4, 5 and 12. [provided by RefSeq, Mar 2016]

PGBD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-49524421-T-A is Pathogenic according to our data. Variant chr10-49524421-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 550722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC6	NM_000124.4	MANE Select	c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 21	NP_000115.1
ERCC6	NM_001277058.2	MANE Plus Clinical	c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 6	NP_001263987.1
ERCC6	NM_001346440.2		c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 21	NP_001333369.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 21	ENSP00000348089.5
ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 6	ENSP00000387966.2
ERCC6	ENST00000681659.1		c.1009A>T	p.Lys337*	stop_gained	Exon 5 of 20	ENSP00000505631.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251420

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebrooculofacioskeletal syndrome 1;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2

Pathogenic:1

Feb 09, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Cerebrooculofacioskeletal syndrome 1;C0242379:Lung cancer;C0265201:DE SANCTIS-CACCHIONE SYNDROME;C0751038:Cockayne syndrome type 2;C3151063:Age related macular degeneration 5;C3551173:UV-sensitive syndrome 1;C4310783:Premature ovarian failure 11

Pathogenic:1

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys337*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 1339317). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550722). For these reasons, this variant has been classified as Pathogenic.

Cockayne syndrome type 2

Pathogenic:1

Feb 22, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Lys337X variant in ERCC6 has been reported in a compound heterozygous state in an individual with Cockayne syndrome, who carried a second pathogenic variant in ERCC6 (Troelstra 1992 PMID: 1339317, Schmickel 1977 PMID: 887325). It has also been identified in 1/113716 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 550722). This nonsense variant leads to a premature termination codon at position 337, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC6 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. An animal model in ERCC6 has shown that a similar variant causes some features of Cockayne Syndrome including photosensitivity, but only mild deficits in growth and neurologic function (van Der Horst 1997 PMID: 9150142). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP criteria applied: PVS1, PM2_Suporting, PM3, PS3_Moderate.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

PhyloP100

2.5

Vest4

0.65

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=1/199

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over