rs1917801

Variant names:

• chr10-49536260-G-A
• rs1917801
• NM_000124.4:c.-15+2702C>T

Variant summary

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

The NM_000124.4(ERCC6):​c.-15+2702C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 152,218 control chromosomes in the GnomAD database, including 824 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 0.089 (824 hom., cov: 32)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 1 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.-15+2702C>T		intron_variant	Intron 1 of 20	ENST00000355832.10	NP_000115.1
ERCC6	NM_001277058.2	c.-15+2702C>T		intron_variant	Intron 1 of 5	ENST00000447839.7	NP_001263987.1
ERCC6	NM_001346440.2	c.-11+2702C>T		intron_variant	Intron 1 of 20		NP_001333369.1
ERCC6	NM_001277059.2	c.-15+3172C>T		intron_variant	Intron 1 of 5		NP_001263988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.-15+2702C>T		intron_variant	Intron 1 of 20	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000447839.7	c.-15+2702C>T		intron_variant	Intron 1 of 5	2	NM_001277058.2	ENSP00000387966.2

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13594 AN: 152100 Hom.: 812 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0856

Gnomad OTH AF: 0.0870

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0895 AC: 13622 AN: 152218 Hom.: 824 Cov.: 32 AF XY: 0.0940 AC XY: 6995 AN XY: 74434

African (AFR) AF: 0.0407 AC: 1691 AN: 41554

American (AMR) AF: 0.190 AC: 2907 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1027 AN: 5162

South Asian (SAS) AF: 0.189 AC: 912 AN: 4826

European-Finnish (FIN) AF: 0.0699 AC: 740 AN: 10588

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0856 AC: 5823 AN: 68010

Other (OTH) AF: 0.0922 AC: 195 AN: 2114

Alfa AF: 0.0928 Hom.: 296

Bravo AF: 0.0973

Asia WGS AF: 0.201 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.43
DANN	Benign	0.61
PhyloP100		-0.29
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: rs1917801; hg19: chr10-50744306;