NM_001277059.2:c.-76C>G

Variant names:

• chr10-49539493-G-C
• rs3793784
• NM_001277059.2:c.-76C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:2
• Conservation: PhyloP100: 2.02
• Publications: 28 publications found

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277059.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_001277059.2		c.-76C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001263988.1
	ERCC6	NM_001277059.2		c.-76C>G		5_prime_UTR	Exon 1 of 6	NP_001263988.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000515869.1	TSL:2	c.-76C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000423550.1
	ERCC6	ENST00000462247.1	TSL:3	c.-76C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000422827.1
	ERCC6	ENST00000515869.1	TSL:2	c.-76C>G		5_prime_UTR	Exon 1 of 6	ENSP00000423550.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45505 AN: 151916 Hom.: 8408 Cov.: 32

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: 53 AN: 148 Hom.: 11 Cov.: 0 AF XY: 0.349 AC XY: 37 AN XY: 106

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.429 AC: 6 AN: 14

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.367 AC: 44 AN: 120

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.299 AC: 45479 AN: 152034 Hom.: 8399 Cov.: 32 AF XY: 0.297 AC XY: 22064 AN XY: 74314

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

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:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.6
DANN	Benign	0.57
PhyloP100		2.0
PromoterAI		0.0020	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3793784; hg19: chr10-50747539;