11-47215239-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000107.3(DDB2):c.103A>G(p.Lys35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DDB2
NM_000107.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue N6-acetyllysine (size 0) in uniprot entity DDB2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18649057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDB2	NM_000107.3 linkuse as main transcript	c.103A>G	p.Lys35Glu	missense_variant	1/10	ENST00000256996.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDB2	ENST00000256996.9 linkuse as main transcript	c.103A>G	p.Lys35Glu	missense_variant	1/10	1	NM_000107.3	P1	Q92466-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251256

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.103A>G (p.K35E) alteration is located in exon 1 (coding exon 1) of the DDB2 gene. This alteration results from a A to G substitution at nucleotide position 103, causing the lysine (K) at amino acid position 35 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.045

FATHMM_MKL

Benign

0.092

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationTaster

Benign

0.99

D;D;D;N

PrimateAI

Benign

0.44

Sift4G

Pathogenic

0.0

D;D;T;D;T;T

Polyphen

0.15, 0.83, 0.56

.;.;B;.;P;P

Vest4

0.26, 0.18, 0.30

MutPred

0.21

Loss of ubiquitination at K35 (P = 0.0103);Loss of ubiquitination at K35 (P = 0.0103);Loss of ubiquitination at K35 (P = 0.0103);Loss of ubiquitination at K35 (P = 0.0103);Loss of ubiquitination at K35 (P = 0.0103);Loss of ubiquitination at K35 (P = 0.0103);

MVP

0.90

MPC

0.53

ClinPred

0.47

GERP RS

3.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.63

gMVP

0.63

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

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