chr11-47215268-T-G

Position:

chr11-47215268-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000107.3(DDB2):c.127+5T>G variant causes a splice region, 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_region, intron

Scores

Splicing: ADA: 0.0004350

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.949

Variant links:

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 links:

DDB2 (HGNC:):

DDB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=1, Uncertain_significance=1, 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 GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDB2	NM_000107.3 linkuse as main transcript	c.127+5T>G		splice_region_variant, intron_variant		ENST00000256996.9	NP_000098.1	Q92466-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDB2	ENST00000256996.9 linkuse as main transcript	c.127+5T>G		splice_region_variant, intron_variant		1	NM_000107.3	ENSP00000256996.4		Q92466-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152000

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00155

AC XY:

210

AN XY:

135580

show subpopulations

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.:

Cov.:

AF XY:

0.00172

AC XY:

1251

AN XY:

727212

show subpopulations

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.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74354

show subpopulations

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.:

Bravo

AF:

0.000918

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over