rs11101139

chr10-49478508-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000124.4(ERCC6):c.2170-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,229,700 control chromosomes in the GnomAD database, including 3,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (346 hom., cov: 32)
  • Exomes 𝑓: 0.067 (2906 hom.)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.419

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-49478508-G-A is Benign according to our data. Variant chr10-49478508-G-A is described in ClinVar as [Benign]. Clinvar id is 255164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.2170-38C>T		intron_variant		ENST00000355832.10
ERCC6	NM_001346440.2	c.2170-38C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.2170-38C>T		intron_variant		1	NM_000124.4	P1

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8493 AN: 150422 Hom.: 346 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0900

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.0705

GnomAD3 exomes AF: 0.0535 AC: 13205 AN: 246658 Hom.: 491 AF XY: 0.0540 AC XY: 7224 AN XY: 133734

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.0368

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0824

Gnomad OTH exome AF: 0.0669

GnomAD4 exome AF: 0.0667 AC: 72021 AN: 1079166 Hom.: 2906 Cov.: 15 AF XY: 0.0659 AC XY: 36583 AN XY: 554958

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.0394

Gnomad4 ASJ exome AF: 0.0886

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0640

GnomAD4 genome AF: 0.0564 AC: 8487 AN: 150534 Hom.: 346 Cov.: 32 AF XY: 0.0532 AC XY: 3901 AN XY: 73378

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.0689

Gnomad4 ASJ AF: 0.0900

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.0851

Gnomad4 OTH AF: 0.0697

Alfa AF: 0.0754 Hom.: 90

Bravo AF: 0.0565

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.65

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

LitVar

Other links and lift over

dbSNP: rs11101139; hg19: chr10-50686554;