chr10-49478508-G-A

Variant names:

• chr10-49478508-G-A
• rs11101139
• NM_000124.4:c.2170-38C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.419
• Publications: 2 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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	NM_000124.4	MANE Select	c.2170-38C>T		intron	N/A	NP_000115.1
	ERCC6	NM_001346440.2		c.2170-38C>T		intron	N/A	NP_001333369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC6	ENST00000355832.10	TSL:1 MANE Select	c.2170-38C>T		intron	N/A	ENSP00000348089.5
	ERCC6	ENST00000623073.3	TSL:1	n.6650-38C>T		intron	N/A
	ERCC6	ENST00000681659.1		c.2011-38C>T		intron	N/A	ENSP00000505631.1

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

GnomAD2 exomes AF: 0.0535 AC: 13205 AN: 246658 AF XY: 0.0540

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 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

African (AFR) AF: 0.0127 AC: 331 AN: 26160

American (AMR) AF: 0.0394 AC: 1739 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.0886 AC: 2101 AN: 23702

East Asian (EAS) AF: 0.00 AC: 0 AN: 37688

South Asian (SAS) AF: 0.0169 AC: 1335 AN: 78868

European-Finnish (FIN) AF: 0.0373 AC: 1716 AN: 45992

Middle Eastern (MID) AF: 0.0691 AC: 346 AN: 5008

European-Non Finnish (NFE) AF: 0.0798 AC: 61401 AN: 769854

Other (OTH) AF: 0.0640 AC: 3052 AN: 47718

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

African (AFR) AF: 0.0151 AC: 616 AN: 40840

American (AMR) AF: 0.0689 AC: 1042 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 311 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.0185 AC: 88 AN: 4762

European-Finnish (FIN) AF: 0.0290 AC: 296 AN: 10190

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0851 AC: 5770 AN: 67788

Other (OTH) AF: 0.0697 AC: 145 AN: 2080

Alfa AF: 0.0754 Hom.: 90

Bravo AF: 0.0565

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11101139; hg19: chr10-50686554;