rs2274097

Variant names:

• chr10-49471035-G-A
• rs2274097
• NM_000124.4:c.3010C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-49471035-G-A
• chr10-49471035-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000124.4(ERCC6):​c.3010C>T​(p.Leu1004Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,614,068 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1004L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (142 hom.)
• Consequence: ERCC6 NM_000124.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.09
• Publications: 7 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 10-49471035-G-A is Benign according to our data. Variant chr10-49471035-G-A is described in ClinVar as Benign. ClinVar VariationId is 194696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0692 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.3010C>T	p.Leu1004Leu	synonymous	Exon 17 of 21	NP_000115.1
	ERCC6	NM_001346440.2		c.3010C>T	p.Leu1004Leu	synonymous	Exon 17 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.3010C>T	p.Leu1004Leu	synonymous	Exon 17 of 21	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.7394C>T		non_coding_transcript_exon	Exon 11 of 15
	ERCC6	ENST00000624341.3	TSL:1	n.*609C>T		non_coding_transcript_exon	Exon 7 of 11	ENSP00000485163.1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 821 AN: 152192 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0123 AC: 3097 AN: 251200 AF XY: 0.0107

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0789

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.000749

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00367 AC: 5359 AN: 1461758 Hom.: 142 Cov.: 33 AF XY: 0.00349 AC XY: 2537 AN XY: 727188

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.0324 AC: 1451 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26130

East Asian (EAS) AF: 0.0675 AC: 2679 AN: 39682

South Asian (SAS) AF: 0.000614 AC: 53 AN: 86256

European-Finnish (FIN) AF: 0.0123 AC: 657 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000188 AC: 209 AN: 1111950

Other (OTH) AF: 0.00467 AC: 282 AN: 60390

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152310 Hom.: 20 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74480

African (AFR) AF: 0.000601 AC: 25 AN: 41578

American (AMR) AF: 0.0135 AC: 207 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0754 AC: 391 AN: 5186

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00369 Hom.: 12

Bravo AF: 0.00641

Asia WGS AF: 0.0230 AC: 81 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Age related macular degeneration 5 (1)
-	-	1	Cerebrooculofacioskeletal syndrome 1 (1)
-	-	1	Cockayne syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.1
DANN	Benign	0.76
PhyloP100		8.1
Mutation Taster		=77/23	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: rs2274097; hg19: chr10-50679081;