rs886048361
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000107.3(DDB2):c.914C>A(p.Thr305Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T305T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
DDB2
NM_000107.3 missense
NM_000107.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 4.64
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.862
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDB2 | NM_000107.3 | c.914C>A | p.Thr305Asn | missense_variant | 7/10 | ENST00000256996.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDB2 | ENST00000256996.9 | c.914C>A | p.Thr305Asn | missense_variant | 7/10 | 1 | NM_000107.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135912
GnomAD3 exomes
AF:
AC:
1
AN:
251472
Hom.:
AF XY:
AC XY:
0
AN XY:
135912
Gnomad AFR exome
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GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The DDB2 c.914C>A (p.Thr305Asn) missense variant has been reported in one study in which it was identified in a homozygous state in one of four individuals diagnosed with xeroderma pigmentosum (Oh et al. 2011). Family studies revealed that the patient's parents and unaffected brother were heterozygous for the variant. Control data are not available for this variant which is reported at a frequency of 0.000099 in the Ashkenazi Jewish population of the Genome Aggregation Database, although this is based on only one allele in a region of good sequence coverage so the variant is presumed to be rare. The evidence for this variant is limited. The p.Thr305Asn variant is therefore classified as a variant of unknown significance, but suspicious for pathogenicity for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of phosphorylation at T305 (P = 0.1127);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at