10-49458762-A-G

Variant names:

• chr10-49458762-A-G
• rs4253231
• ENST00000623073.3:n.8919T>C

Variant summary

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

The ENST00000623073.3(ERCC6):​n.8919T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,557,202 control chromosomes in the GnomAD database, including 9,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (888 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8535 hom.)
• Consequence: ERCC6 ENST00000623073.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.478
• Publications: 19 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=-0.78).
• BP6: Variant 10-49458762-A-G is Benign according to our data. Variant chr10-49458762-A-G is described in ClinVar as Benign. ClinVar VariationId is 300031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.*53T>C		3_prime_UTR_variant	Exon 21 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.*53T>C		3_prime_UTR_variant	Exon 21 of 21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.*53T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15609 AN: 152140 Hom.: 882 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0701

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.0914

GnomAD4 exome AF: 0.103 AC: 144284 AN: 1404944 Hom.: 8535 Cov.: 24 AF XY: 0.104 AC XY: 73369 AN XY: 702242

African (AFR) AF: 0.110 AC: 3547 AN: 32248

American (AMR) AF: 0.171 AC: 7628 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 2155 AN: 25714

East Asian (EAS) AF: 0.186 AC: 7335 AN: 39414

South Asian (SAS) AF: 0.191 AC: 16101 AN: 84298

European-Finnish (FIN) AF: 0.0743 AC: 3957 AN: 53230

Middle Eastern (MID) AF: 0.0773 AC: 437 AN: 5652

European-Non Finnish (NFE) AF: 0.0912 AC: 96819 AN: 1061382

Other (OTH) AF: 0.108 AC: 6305 AN: 58484

GnomAD4 genome AF: 0.103 AC: 15637 AN: 152258 Hom.: 888 Cov.: 32 AF XY: 0.105 AC XY: 7819 AN XY: 74450

African (AFR) AF: 0.110 AC: 4575 AN: 41518

American (AMR) AF: 0.144 AC: 2206 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.164 AC: 850 AN: 5190

South Asian (SAS) AF: 0.188 AC: 908 AN: 4824

European-Finnish (FIN) AF: 0.0701 AC: 744 AN: 10610

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0856 AC: 5820 AN: 68024

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.0943 Hom.: 2926

Bravo AF: 0.108

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

COFS syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cockayne syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.8
DANN	Benign	0.84
PhyloP100		-0.48
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: rs4253231; hg19: chr10-50666808; COSMIC: COSV63388659; COSMIC: COSV63388659;