rs4253212

chr10-49470166-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.3778+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,610,482 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (188 hom.)
• Consequence: ERCC6 NM_000124.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.33

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 10-49470166-G-A is Benign according to our data. Variant chr10-49470166-G-A is described in ClinVar as [Benign]. Clinvar id is 255166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49470166-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC6	NM_000124.4	c.3778+16C>T		intron_variant		ENST00000355832.10
ERCC6	NM_001346440.2	c.3778+16C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC6	ENST00000355832.10	c.3778+16C>T		intron_variant		1	NM_000124.4	P1
	ENST00000423283.1	n.235-2537G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00484 AC: 736 AN: 152158 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.0115 AC: 2884 AN: 251178 Hom.: 130 AF XY: 0.0101 AC XY: 1373 AN XY: 135762

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00327 AC: 4763 AN: 1458206 Hom.: 188 Cov.: 30 AF XY: 0.00314 AC XY: 2278 AN XY: 725712

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.0842

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000685

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.00483 AC: 735 AN: 152276 Hom.: 37 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74448

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.00614

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.12
Dann	Benign	0.67

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

Other links and lift over

dbSNP: rs4253212; hg19: chr10-50678212; COSMIC: COSV63387920;