10-49470301-G-A

Variant names:

• chr10-49470301-G-A
• rs34704611
• NM_000124.4:c.3659C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000124.4(ERCC6):​c.3659C>T​(p.Thr1220Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,614,080 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1220T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (12 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.78
• Publications: 5 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 (MetaRNN=0.008501083).
• BP6: Variant 10-49470301-G-A is Benign according to our data. Variant chr10-49470301-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1279/152300) while in subpopulation AFR AF = 0.029 (1203/41536). AF 95% confidence interval is 0.0276. There are 21 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR,Unknown gene

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.3659C>T	p.Thr1220Ile	missense	Exon 18 of 21	NP_000115.1
	ERCC6	NM_001346440.2		c.3659C>T	p.Thr1220Ile	missense	Exon 18 of 21	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.3659C>T	p.Thr1220Ile	missense	Exon 18 of 21	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.8043C>T		non_coding_transcript_exon	Exon 12 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*1258C>T		non_coding_transcript_exon	Exon 8 of 11	ENSP00000485163.1

Frequencies

GnomAD3 genomes AF: 0.00836 AC: 1273 AN: 152182 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00209 AC: 526 AN: 251322 AF XY: 0.00150

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000801 AC: 1171 AN: 1461780 Hom.: 12 Cov.: 32 AF XY: 0.000667 AC XY: 485 AN XY: 727194

African (AFR) AF: 0.0280 AC: 938 AN: 33452

American (AMR) AF: 0.00190 AC: 85 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

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

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111982

Other (OTH) AF: 0.00164 AC: 99 AN: 60388

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152300 Hom.: 21 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74476

African (AFR) AF: 0.0290 AC: 1203 AN: 41536

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68040

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00294 Hom.: 9

Bravo AF: 0.00971

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely 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

Jul 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.32	T
Sift4G	Benign	0.26	T
Polyphen		0.85	P
Vest4		0.15
MVP		0.79
MPC		0.11
ClinPred		0.031	T
GERP RS		4.8
Varity_R		0.085
gMVP		0.14
Mutation Taster		=98/2	polymorphism

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: rs34704611; hg19: chr10-50678347; COSMIC: COSV99054197; COSMIC: COSV99054197;