rs143049891

Positions:

chr11-47238177-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000107.3(DDB2):c.1228G>A(p.Ala410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,610,774 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 19 hom. )

Consequence

DDB2
NM_000107.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:1

Conservation

PhyloP100: 1.19

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008513182).

BP6

Variant 11-47238177-G-A is Benign according to our data. Variant chr11-47238177-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (385/152308) while in subpopulation NFE AF= 0.00395 (269/68016). AF 95% confidence interval is 0.00357. There are 0 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDB2	NM_000107.3 linkuse as main transcript	c.1228G>A	p.Ala410Thr	missense_variant	9/10	ENST00000256996.9	NP_000098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDB2	ENST00000256996.9 linkuse as main transcript	c.1228G>A	p.Ala410Thr	missense_variant	9/10	1	NM_000107.3	ENSP00000256996	P1	Q92466-1

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

385

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00395

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00255

AC:

624

AN:

244966

Hom.:

AF XY:

0.00233

AC XY:

308

AN XY:

132272

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00192

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00215

Gnomad NFE exome

AF:

0.00430

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.00378

AC:

5520

AN:

1458466

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

2668

AN XY:

725198

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000304

Gnomad4 FIN exome

AF:

0.00220

Gnomad4 NFE exome

AF:

0.00458

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152308

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00395

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00282

AC:

343

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DDB2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	This variant is associated with the following publications: (PMID: 24728327) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DDB2 p.Ala410Thr variant was not identified in the literature nor was it identified in LOVD 3.0 or Cosmic. The variant was identified in dbSNP (ID: rs143049891) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 690 of 276356 chromosomes (2 homozygous) at a frequency of 0.002497 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 526 of 126090 chromosomes (freq: 0.004172), European (Finnish) in 52 of 24444 chromosomes (freq: 0.002127), Other in 14 of 7086 chromosomes (freq: 0.001976), Latino in 66 of 34698 chromosomes (freq: 0.001902), African in 27 of 24524 chromosomes (freq: 0.001101) and South Asian in 5 of 29572 chromosomes (freq: 0.000169), but was not observed in the Ashkenazi Jewish, or East Asian populations. The p.Ala410 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2023	- -

Xeroderma pigmentosum, group E

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Xeroderma pigmentosum

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 12, 2021

- -

DDB2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0085

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;.;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.27

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.18

MVP

0.36

MPC

0.36

ClinPred

0.021

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.59

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