rs4253160

Variant names:

• chr10-49485920-T-A
• rs4253160
• NM_000124.4:c.1822-2404A>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.1822-2404A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,122 control chromosomes in the GnomAD database, including 9,368 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 0.32 (9368 hom., cov: 32)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183
• Publications: 4 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: Myriad Women's Health, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.1822-2404A>T		intron	N/A	NP_000115.1	Q03468-1
	ERCC6	NM_001346440.2		c.1822-2404A>T		intron	N/A	NP_001333369.1	Q03468-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.1822-2404A>T		intron	N/A	ENSP00000348089.5	Q03468-1
	ERCC6	ENST00000623073.3	TSL:1	n.6301+2238A>T		intron	N/A
	ERCC6	ENST00000898255.1		c.1822-2404A>T		intron	N/A	ENSP00000568314.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47963 AN: 152004 Hom.: 9375 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.315 AC: 47941 AN: 152122 Hom.: 9368 Cov.: 32 AF XY: 0.313 AC XY: 23288 AN XY: 74330

African (AFR) AF: 0.0834 AC: 3463 AN: 41542

American (AMR) AF: 0.317 AC: 4836 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1237 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1643 AN: 5178

South Asian (SAS) AF: 0.264 AC: 1273 AN: 4818

European-Finnish (FIN) AF: 0.417 AC: 4400 AN: 10562

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29796 AN: 67966

Other (OTH) AF: 0.333 AC: 703 AN: 2110

Alfa AF: 0.361 Hom.: 1404

Bravo AF: 0.300

Asia WGS AF: 0.275 AC: 957 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.7
DANN	Benign	0.72
PhyloP100		-0.18
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4253160;

hg19: chr10-50693966;