NM_000124.4:c.1398-3528G>A

Variant names:

• chr10-49509540-C-T
• rs4253082
• NM_000124.4:c.1398-3528G>A

Variant summary

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

The NM_000124.4(ERCC6):​c.1398-3528G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,042 control chromosomes in the GnomAD database, including 4,758 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 0.23 (4758 hom., cov: 32)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.1398-3528G>A		intron_variant	Intron 5 of 20	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.1398-3528G>A		intron_variant	Intron 5 of 20		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.1398-3528G>A		intron_variant	Intron 5 of 20	1	NM_000124.4	ENSP00000348089.5
ERCC6	ENST00000681659.1	c.1398-3528G>A		intron_variant	Intron 5 of 19			ENSP00000505631.1
ERCC6	ENST00000679811.1	n.1481-3528G>A		intron_variant	Intron 5 of 5
ERCC6	ENST00000681632.1	n.1476-3528G>A		intron_variant	Intron 5 of 17

Frequencies

GnomAD3 genomes AF: 0.230 AC: 35013 AN: 151924 Hom.: 4751 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.231 AC: 35058 AN: 152042 Hom.: 4758 Cov.: 32 AF XY: 0.229 AC XY: 16991 AN XY: 74292

African (AFR) AF: 0.343 AC: 14230 AN: 41462

American (AMR) AF: 0.244 AC: 3730 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2396 AN: 5158

South Asian (SAS) AF: 0.142 AC: 684 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10562

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11108 AN: 67990

Other (OTH) AF: 0.229 AC: 483 AN: 2110

Alfa AF: 0.185 Hom.: 5405

Bravo AF: 0.246

Asia WGS AF: 0.308 AC: 1071 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.0
DANN	Benign	0.30
PhyloP100		-0.58
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: rs4253082; hg19: chr10-50717586; COSMIC: COSV63390774; COSMIC: COSV63390774;