10-49470166-G-A

Variant names:

• chr10-49470166-G-A
• rs4253212
• NM_000124.4:c.3778+16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.3778+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,610,482 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (188 hom.)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.33
• Publications: 11 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)

ENSG00000235939 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-49470166-G-A is Benign according to our data. Variant chr10-49470166-G-A is described in ClinVar as Benign. ClinVar VariationId is 255166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.3778+16C>T		intron	N/A	NP_000115.1
	ERCC6	NM_001346440.2		c.3778+16C>T		intron	N/A	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.3778+16C>T		intron	N/A	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.8162+16C>T		intron	N/A
	ERCC6	ENST00000624341.3	TSL:1	n.*1377+16C>T		intron	N/A	ENSP00000485163.1

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152158 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.0115 AC: 2884 AN: 251178 AF XY: 0.0101

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00327 AC: 4763 AN: 1458206 Hom.: 188 Cov.: 30 AF XY: 0.00314 AC XY: 2278 AN XY: 725712

African (AFR) AF: 0.000569 AC: 19 AN: 33416

American (AMR) AF: 0.0178 AC: 796 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26112

East Asian (EAS) AF: 0.0842 AC: 3342 AN: 39682

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000685 AC: 76 AN: 1108718

Other (OTH) AF: 0.00518 AC: 312 AN: 60256

GnomAD4 genome AF: 0.00483 AC: 735 AN: 152276 Hom.: 37 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74448

African (AFR) AF: 0.000770 AC: 32 AN: 41562

American (AMR) AF: 0.00680 AC: 104 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.108 AC: 560 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.00614

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.12
DANN	Benign	0.67
PhyloP100		-2.3
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: rs4253212; hg19: chr10-50678212; COSMIC: COSV63387920;