11-47215219-T-TG

Variant names:

• chr11-47215219-T-TG
• NM_000107.3:c.85dupG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000107.3(DDB2):​c.85dupG​(p.Glu29GlyfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DDB2 NM_000107.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0270
• Publications: 0 publications found

Genes affected

DDB2 (HGNC:2718): (damage specific DNA binding protein 2) This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

DDB2 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group E

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47215219-T-TG is Pathogenic according to our data. Variant chr11-47215219-T-TG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2431840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000107.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB2	NM_000107.3	MANE Select	c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 1 of 10	NP_000098.1	Q92466-1
	DDB2	NM_001399874.1		c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 2 of 11	NP_001386803.1	Q92466-1
	DDB2	NM_001399875.1		c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 2 of 11	NP_001386804.1	Q92466-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DDB2	ENST00000256996.9	TSL:1 MANE Select	c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 1 of 10	ENSP00000256996.4	Q92466-1
	DDB2	ENST00000378603.7	TSL:1	c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 1 of 9	ENSP00000367866.3	Q92466-4
	DDB2	ENST00000378600.7	TSL:1	c.85dupG	p.Glu29GlyfsTer17	frameshift	Exon 1 of 6	ENSP00000367863.3	Q92466-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Xeroderma pigmentosum, group E (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.027

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

hg19: chr11-47236770;