Genetic Variant NM_002874.5:c.746C>T (chr9-107322047-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002874.5(RAD23B):c.746C>T(p.Ala249Val) variant causes a missense change. The variant allele was found at a frequency of 0.192 in 1,611,794 control chromosomes in the GnomAD database, including 31,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2366 hom., cov: 33)

Exomes 𝑓: 0.20 ( 29456 hom. )

Consequence

RAD23B
NM_002874.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.80

Publications

83 publications found

Variant links:

Genes affected

RAD23B (HGNC:9813): (RAD23 homolog B, nucleotide excision repair protein) The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in the nucleotide excision repair (NER). This protein was found to be a component of the protein complex that specifically complements the NER defect of xeroderma pigmentosum group C (XP-c) cell extracts in vitro. This protein was also shown to interact with, and elevate the nucleotide excision activity of 3-methyladenine-DNA glycosylase (MPG), which suggested a role in DNA damage recognition in base excision repair. This protein contains an N-terminal ubiquitin-like domain, which was reported to interact with 26S proteasome, and thus this protein may be involved in the ubiquitin mediated proteolytic pathway in cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Sep 2011]

RAD23B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034525692).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD23B	NM_002874.5 link	c.746C>T	p.Ala249Val	missense_variant	Exon 7 of 10	ENST00000358015.8	NP_002865.1	P54727-1
RAD23B	NM_001244713.1 link	c.683C>T	p.Ala228Val	missense_variant	Exon 7 of 10		NP_001231642.1	B7Z4W4
RAD23B	NM_001244724.2 link	c.530C>T	p.Ala177Val	missense_variant	Exon 7 of 10		NP_001231653.1	P54727-2B7Z4W4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAD23B	ENST00000358015.8 link	c.746C>T	p.Ala249Val	missense_variant	Exon 7 of 10	1	NM_002874.5	ENSP00000350708.3	P54727-1
RAD23B	ENST00000416373.6 link	c.530C>T	p.Ala177Val	missense_variant	Exon 7 of 10	1		ENSP00000405623.2	P54727-2
RAD23B	ENST00000457811.1 link	c.288+3168C>T		intron_variant	Intron 3 of 3	3		ENSP00000396975.1	H0Y579

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23931

AN:

152048

Hom.:

2366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.180

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.133

GnomAD2 exomes

AF:

0.199

AC:

49753

AN:

249664

AF XY:

0.196

show subpopulations

Gnomad AFR exome

AF:

0.0383

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.0886

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.192

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.195

AC:

284984

AN:

1459630

Hom.:

29456

Cov.:

AF XY:

0.195

AC XY:

141582

AN XY:

726090

show subpopulations

African (AFR)

AF:

0.0299

AC:

1001

AN:

33438

American (AMR)

AF:

0.309

AC:

13715

AN:

44344

Ashkenazi Jewish (ASJ)

AF:

0.0901

AC:

2353

AN:

26104

East Asian (EAS)

AF:

0.185

AC:

7317

AN:

39556

South Asian (SAS)

AF:

0.193

AC:

16545

AN:

85882

European-Finnish (FIN)

AF:

0.245

AC:

13093

AN:

53364

Middle Eastern (MID)

AF:

0.111

AC:

640

AN:

5764

European-Non Finnish (NFE)

AF:

0.198

AC:

219714

AN:

1110874

Other (OTH)

AF:

0.176

AC:

10606

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

10959

21918

32876

43835

54794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7620

15240

22860

30480

38100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.157

AC:

23933

AN:

152164

Hom.:

2366

Cov.:

AF XY:

0.161

AC XY:

11963

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0385

AC:

1597

AN:

41530

American (AMR)

AF:

0.231

AC:

3526

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3470

East Asian (EAS)

AF:

0.185

AC:

958

AN:

5172

South Asian (SAS)

AF:

0.179

AC:

865

AN:

4822

European-Finnish (FIN)

AF:

0.247

AC:

2611

AN:

10574

Middle Eastern (MID)

AF:

0.106

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.200

AC:

13630

AN:

67990

Other (OTH)

AF:

0.133

AC:

281

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1004

2008

3012

4016

5020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.173

Hom.:

1224

Bravo

AF:

0.151

TwinsUK

AF:

0.186

AC:

691

ALSPAC

AF:

0.189

AC:

727

ESP6500AA

AF:

0.0490

AC:

216

ESP6500EA

AF:

0.183

AC:

1577

ExAC

AF:

0.195

AC:

23681

Asia WGS

AF:

0.171

AC:

595

AN:

3478

EpiCase

AF:

0.177

EpiControl

AF:

0.175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.095

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.0

M;.

PhyloP100

3.8

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.99

N;N

REVEL

Benign

0.061

Sift

Benign

0.23

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.30

B;.

Vest4

0.037

MPC

0.50

ClinPred

0.023

GERP RS

5.3

Varity_R

0.076

gMVP

0.35

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over