rs2291120

Variant names:

• chr11-47216129-T-C
• rs2291120
• NM_000107.3:c.128-207T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000107.3(DDB2):​c.128-207T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 746,076 control chromosomes in the GnomAD database, including 5,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (997 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4744 hom.)
• Consequence: DDB2 NM_000107.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.723
• Publications: 18 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), ClinGen, Genomics England PanelApp
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-47216129-T-C is Benign according to our data. Variant chr11-47216129-T-C is described in ClinVar as Benign. ClinVar VariationId is 1276638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDB2	NM_000107.3	c.128-207T>C		intron_variant	Intron 1 of 9	ENST00000256996.9	NP_000098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDB2	ENST00000256996.9	c.128-207T>C		intron_variant	Intron 1 of 9	1	NM_000107.3	ENSP00000256996.4

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15168 AN: 152074 Hom.: 992 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.0830

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.120 AC: 71357 AN: 593882 Hom.: 4744 Cov.: 7 AF XY: 0.119 AC XY: 38406 AN XY: 321430

African (AFR) AF: 0.0259 AC: 446 AN: 17230

American (AMR) AF: 0.163 AC: 6284 AN: 38632

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 1667 AN: 18906

East Asian (EAS) AF: 0.0262 AC: 914 AN: 34860

South Asian (SAS) AF: 0.112 AC: 7174 AN: 64278

European-Finnish (FIN) AF: 0.147 AC: 5170 AN: 35242

Middle Eastern (MID) AF: 0.131 AC: 457 AN: 3482

European-Non Finnish (NFE) AF: 0.130 AC: 45366 AN: 349290

Other (OTH) AF: 0.121 AC: 3879 AN: 31962

GnomAD4 genome AF: 0.0997 AC: 15177 AN: 152194 Hom.: 997 Cov.: 32 AF XY: 0.0995 AC XY: 7401 AN XY: 74416

African (AFR) AF: 0.0260 AC: 1082 AN: 41556

American (AMR) AF: 0.146 AC: 2234 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 288 AN: 3468

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5180

South Asian (SAS) AF: 0.113 AC: 543 AN: 4826

European-Finnish (FIN) AF: 0.143 AC: 1511 AN: 10592

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8823 AN: 67990

Other (OTH) AF: 0.125 AC: 265 AN: 2116

Alfa AF: 0.118 Hom.: 2462

Bravo AF: 0.0969

Asia WGS AF: 0.0960 AC: 336 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs2291120; hg19: chr11-47237680;