NM_000124.4:c.1821+2466T>G

Variant names:

• chr10-49490651-A-C
• rs7072383
• NM_000124.4:c.1821+2466T>G

Variant summary

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

The NM_000124.4(ERCC6):​c.1821+2466T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 152,190 control chromosomes in the GnomAD database, including 57,413 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 0.86 (57413 hom., cov: 33)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0130
• Publications: 2 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.1821+2466T>G		intron_variant	Intron 8 of 20	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.1821+2466T>G		intron_variant	Intron 8 of 20		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.1821+2466T>G		intron_variant	Intron 8 of 20	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes AF: 0.864 AC: 131456 AN: 152072 Hom.: 57392 Cov.: 33

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.841

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.955

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.887

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

GnomAD4 genome AF: 0.864 AC: 131525 AN: 152190 Hom.: 57413 Cov.: 33 AF XY: 0.870 AC XY: 64719 AN XY: 74390

African (AFR) AF: 0.730 AC: 30301 AN: 41504

American (AMR) AF: 0.924 AC: 14132 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 3012 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5174

South Asian (SAS) AF: 0.955 AC: 4599 AN: 4818

European-Finnish (FIN) AF: 0.930 AC: 9857 AN: 10594

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61546 AN: 68018

Other (OTH) AF: 0.888 AC: 1877 AN: 2114

Alfa AF: 0.876 Hom.: 7319

Bravo AF: 0.857

Asia WGS AF: 0.964 AC: 3351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-0.013
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: rs7072383; hg19: chr10-50698697;