dbSNP rs4253013: ERCC6:p.Leu137Leu (chr10-49532554-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000124.4(ERCC6):c.411G>A(p.Leu137Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,613,920 control chromosomes in the GnomAD database, including 8,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1174 hom., cov: 33)

Exomes 𝑓: 0.081 ( 7669 hom. )

Consequence

ERCC6
NM_000124.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.372

Publications

31 publications found

Variant links:

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)

ERCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 10-49532554-C-T is Benign according to our data. Variant chr10-49532554-C-T is described in ClinVar as Benign. ClinVar VariationId is 129019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.372 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC6	NM_000124.4	MANE Select	c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 21	NP_000115.1
ERCC6	NM_001277058.2	MANE Plus Clinical	c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 6	NP_001263987.1
ERCC6	NM_001346440.2		c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 21	NP_001333369.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 21	ENSP00000348089.5
ERCC6	ENST00000447839.7	TSL:2 MANE Plus Clinical	c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 6	ENSP00000387966.2
ERCC6	ENST00000898255.1		c.411G>A	p.Leu137Leu	synonymous	Exon 2 of 21	ENSP00000568314.1

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15639

AN:

152108

Hom.:

1175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.0747

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0638

Gnomad OTH

AF:

0.110

GnomAD2 exomes

AF:

0.128

AC:

32050

AN:

251180

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.0781

Gnomad EAS exome

AF:

0.402

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.0619

Gnomad OTH exome

AF:

0.0981

GnomAD4 exome

AF:

0.0813

AC:

118907

AN:

1461694

Hom.:

7669

Cov.:

AF XY:

0.0810

AC XY:

58873

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.104

AC:

3487

AN:

33480

American (AMR)

AF:

0.253

AC:

11312

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0792

AC:

2070

AN:

26136

East Asian (EAS)

AF:

0.347

AC:

13780

AN:

39700

South Asian (SAS)

AF:

0.0965

AC:

8328

AN:

86258

European-Finnish (FIN)

AF:

0.109

AC:

5807

AN:

53232

Middle Eastern (MID)

AF:

0.0697

AC:

402

AN:

5768

European-Non Finnish (NFE)

AF:

0.0612

AC:

68065

AN:

1112006

Other (OTH)

AF:

0.0936

AC:

5656

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

7346

14692

22039

29385

36731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2890

5780

8670

11560

14450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.103

AC:

15652

AN:

152226

Hom.:

1174

Cov.:

AF XY:

0.108

AC XY:

8001

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.106

AC:

4410

AN:

41526

American (AMR)

AF:

0.171

AC:

2610

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0747

AC:

259

AN:

3468

East Asian (EAS)

AF:

0.385

AC:

1991

AN:

5170

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4824

European-Finnish (FIN)

AF:

0.114

AC:

1208

AN:

10604

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0638

AC:

4337

AN:

68022

Other (OTH)

AF:

0.112

AC:

237

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

675

1350

2026

2701

3376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0802

Hom.:

575

Bravo

AF:

0.111

Asia WGS

AF:

0.242

AC:

843

AN:

3478

EpiCase

AF:

0.0622

EpiControl

AF:

0.0598

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Cerebrooculofacioskeletal syndrome 1 (1)

Cockayne syndrome (1)

Cockayne syndrome type 2 (1)

COFS syndrome (1)

DE SANCTIS-CACCHIONE SYNDROME (1)

Macular degeneration (1)

UV-sensitive syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over