rs4253211

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000124.4(ERCC6):c.3689G>C(p.Arg1230Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 1,613,988 control chromosomes in the GnomAD database, including 7,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1230C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.065 ( 433 hom., cov: 32)

Exomes 𝑓: 0.093 ( 6977 hom. )

Consequence

ERCC6
NM_000124.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.542

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027070343).

BP6

Variant 10-49470271-C-G is Benign according to our data. Variant chr10-49470271-C-G is described in ClinVar as [Benign]. Clinvar id is 129018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49470271-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4 linkuse as main transcript	c.3689G>C	p.Arg1230Pro	missense_variant	18/21	ENST00000355832.10
ERCC6	NM_001346440.2 linkuse as main transcript	c.3689G>C	p.Arg1230Pro	missense_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10 linkuse as main transcript	c.3689G>C	p.Arg1230Pro	missense_variant	18/21	1	NM_000124.4	P1	Q03468-1
	ENST00000423283.1 linkuse as main transcript	n.235-2432C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0647

AC:

9846

AN:

152124

Hom.:

434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0804

Gnomad EAS

AF:

0.0804

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.0456

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0985

Gnomad OTH

AF:

0.0694

GnomAD3 exomes

AF:

0.0712

AC:

17882

AN:

251302

Hom.:

792

AF XY:

0.0712

AC XY:

9668

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0764

Gnomad EAS exome

AF:

0.0690

Gnomad SAS exome

AF:

0.0423

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0787

GnomAD4 exome

AF:

0.0931

AC:

136149

AN:

1461746

Hom.:

6977

Cov.:

AF XY:

0.0916

AC XY:

66580

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.0384

Gnomad4 ASJ exome

AF:

0.0776

Gnomad4 EAS exome

AF:

0.101

Gnomad4 SAS exome

AF:

0.0425

Gnomad4 FIN exome

AF:

0.0547

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.0837

GnomAD4 genome

AF:

0.0646

AC:

9837

AN:

152242

Hom.:

433

Cov.:

AF XY:

0.0602

AC XY:

4480

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0203

Gnomad4 AMR

AF:

0.0459

Gnomad4 ASJ

AF:

0.0804

Gnomad4 EAS

AF:

0.0801

Gnomad4 SAS

AF:

0.0365

Gnomad4 FIN

AF:

0.0456

Gnomad4 NFE

AF:

0.0985

Gnomad4 OTH

AF:

0.0672

Alfa

AF:

0.0822

Hom.:

436

Bravo

AF:

0.0632

TwinsUK

AF:

0.107

AC:

397

ALSPAC

AF:

0.108

AC:

417

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.0962

AC:

827

ExAC

AF:

0.0731

AC:

8879

EpiCase

AF:

0.0955

EpiControl

AF:

0.0952

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Jul 13, 2012	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

COFS syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cockayne syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.38

Cadd

Benign

9.6

Dann

Benign

0.89

DEOGEN2

Benign

0.13

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.3

REVEL

Benign

0.18

Sift

Benign

0.14

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.12

MPC

0.15

ClinPred

0.0048

GERP RS

-7.1

Varity_R

0.22

gMVP

0.28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over