rs326222

Variant names:

• chr11-47238117-T-C
• rs326222
• NM_000107.3:c.1189-21T>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.1189-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,610,336 control chromosomes in the GnomAD database, including 354,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27322 hom., cov: 31)
  • Exomes 𝑓: 0.66 (327454 hom.)
• Consequence: DDB2 NM_000107.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.151
• Publications: 52 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=-0.86).
• BP6: Variant 11-47238117-T-C is Benign according to our data. Variant chr11-47238117-T-C is described in ClinVar as Benign. ClinVar VariationId is 1237094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDB2	NM_000107.3	c.1189-21T>C		intron_variant	Intron 8 of 9	ENST00000256996.9	NP_000098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDB2	ENST00000256996.9	c.1189-21T>C		intron_variant	Intron 8 of 9	1	NM_000107.3	ENSP00000256996.4

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88090 AN: 151896 Hom.: 27301 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.644

GnomAD2 exomes AF: 0.599 AC: 148264 AN: 247400 AF XY: 0.609

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.778

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.662 AC: 965777 AN: 1458322 Hom.: 327454 Cov.: 38 AF XY: 0.661 AC XY: 479460 AN XY: 725356

African (AFR) AF: 0.381 AC: 12757 AN: 33446

American (AMR) AF: 0.566 AC: 25035 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.780 AC: 20342 AN: 26096

East Asian (EAS) AF: 0.258 AC: 10213 AN: 39654

South Asian (SAS) AF: 0.538 AC: 46249 AN: 85898

European-Finnish (FIN) AF: 0.590 AC: 31453 AN: 53290

Middle Eastern (MID) AF: 0.709 AC: 4087 AN: 5764

European-Non Finnish (NFE) AF: 0.700 AC: 776429 AN: 1109662

Other (OTH) AF: 0.651 AC: 39212 AN: 60272

GnomAD4 genome AF: 0.580 AC: 88160 AN: 152014 Hom.: 27322 Cov.: 31 AF XY: 0.571 AC XY: 42437 AN XY: 74300

African (AFR) AF: 0.385 AC: 15974 AN: 41446

American (AMR) AF: 0.628 AC: 9592 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2681 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1312 AN: 5166

South Asian (SAS) AF: 0.535 AC: 2577 AN: 4820

European-Finnish (FIN) AF: 0.573 AC: 6058 AN: 10580

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47599 AN: 67952

Other (OTH) AF: 0.648 AC: 1368 AN: 2110

Alfa AF: 0.594 Hom.: 10651

Bravo AF: 0.576

Asia WGS AF: 0.445 AC: 1549 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Xeroderma pigmentosum, group E Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	-0.86
CADD	Benign	7.5
DANN	Benign	0.68
PhyloP100		0.15
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: rs326222; hg19: chr11-47259668; COSMIC: COSV57040465; COSMIC: COSV57040465;