10-49505013-T-G

Variant names:

• chr10-49505013-T-G
• rs4253101
• ENST00000623073.3:n.1468A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000623073.3(ERCC6):​n.1468A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,100 control chromosomes in the GnomAD database, including 3,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3313 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ERCC6 ENST00000623073.3 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623073.3. 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_000124.4	MANE Select	c.1526+871A>C		intron	N/A	NP_000115.1
	ERCC6	NM_001346440.2		c.1526+871A>C		intron	N/A	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000623073.3	TSL:1	n.1468A>C		non_coding_transcript_exon	Exon 1 of 15
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1526+871A>C		intron	N/A	ENSP00000348089.5
	ERCC6	ENST00000679811.1		n.2480A>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29658 AN: 151982 Hom.: 3309 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.0512

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.215

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.195 AC: 29671 AN: 152100 Hom.: 3313 Cov.: 32 AF XY: 0.203 AC XY: 15067 AN XY: 74360

African (AFR) AF: 0.129 AC: 5344 AN: 41516

American (AMR) AF: 0.208 AC: 3176 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 953 AN: 3466

East Asian (EAS) AF: 0.0513 AC: 266 AN: 5182

South Asian (SAS) AF: 0.347 AC: 1673 AN: 4820

European-Finnish (FIN) AF: 0.283 AC: 2991 AN: 10576

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.216 AC: 14648 AN: 67940

Other (OTH) AF: 0.212 AC: 449 AN: 2114

Alfa AF: 0.139 Hom.: 362

Bravo AF: 0.180

Asia WGS AF: 0.180 AC: 628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4253101; hg19: chr10-50713059;