11-47215268-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000107.3(DDB2):c.127+5T>G variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,918 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: DDB2 NM_000107.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0004350
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.949

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 11-47215268-T-G is Benign according to our data. Variant chr11-47215268-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 695307.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chr11-47215268-T-G is described in Lovd as [Benign]. Variant chr11-47215268-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00143 (217/152118) while in subpopulation NFE AF= 0.00149 (101/67990). AF 95% confidence interval is 0.00125. There are 2 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDB2	NM_000107.3	c.127+5T>G		splice_donor_5th_base_variant, intron_variant		ENST00000256996.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDB2	ENST00000256996.9	c.127+5T>G		splice_donor_5th_base_variant, intron_variant		1	NM_000107.3	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152000 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00802

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00166 AC: 416 AN: 250676 Hom.: 1 AF XY: 0.00155 AC XY: 210 AN XY: 135580

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00729

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00181 AC: 2649 AN: 1461800 Hom.: 2 Cov.: 31 AF XY: 0.00172 AC XY: 1251 AN XY: 727212

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00722

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00143 AC: 217 AN: 152118 Hom.: 2 Cov.: 31 AF XY: 0.00160 AC XY: 119 AN XY: 74354

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00802

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000918

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Mar 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Xeroderma pigmentosum, group E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

Xeroderma pigmentosum Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	18
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.050
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: rs199965459; hg19: chr11-47236819; COSMIC: COSV104563773; COSMIC: COSV104563773;