chr10-49470838-T-A

Variant names:

• chr10-49470838-T-A
• rs139007661
• NM_000124.4:c.3122A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000124.4(ERCC6):​c.3122A>T​(p.Gln1041Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1041P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERCC6 NM_000124.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640
• Publications: 12 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09297699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC6	NM_000124.4	c.3122A>T	p.Gln1041Leu	missense_variant	Exon 18 of 21	ENST00000355832.10	NP_000115.1
ERCC6	NM_001346440.2	c.3122A>T	p.Gln1041Leu	missense_variant	Exon 18 of 21		NP_001333369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC6	ENST00000355832.10	c.3122A>T	p.Gln1041Leu	missense_variant	Exon 18 of 21	1	NM_000124.4	ENSP00000348089.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251060 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461790 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.2
DANN	Benign	0.83
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.064
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.30	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.45		Loss of helix (P = 0.0444);
MVP		0.31
MPC		0.099
ClinPred		0.026	T
GERP RS		-2.1
Varity_R		0.048
gMVP		0.39
Mutation Taster		=97/3	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: rs139007661; hg19: chr10-50678884;