9-107300187-C-G

Variant names:

• chr9-107300187-C-G
• rs1244948800
• NM_002874.5:c.113C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002874.5(RAD23B):​c.113C>G​(p.Ala38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: RAD23B NM_002874.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2186698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD23B	NM_002874.5	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 10	ENST00000358015.8	NP_002865.1
RAD23B	NM_001244713.1	c.50C>G	p.Ala17Gly	missense_variant	Exon 2 of 10		NP_001231642.1
RAD23B	NM_001244724.2	c.-104C>G		5_prime_UTR_variant	Exon 2 of 10		NP_001231653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD23B	ENST00000358015.8	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 10	1	NM_002874.5	ENSP00000350708.3
RAD23B	ENST00000416373	c.-104C>G		5_prime_UTR_variant	Exon 2 of 10	1		ENSP00000405623.2
RAD23B	ENST00000419616.5	c.113C>G	p.Ala38Gly	missense_variant	Exon 3 of 5	3		ENSP00000416868.1
RAD23B	ENST00000442587.1	c.50C>G	p.Ala17Gly	missense_variant	Exon 2 of 4	2		ENSP00000415821.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113C>G (p.A38G) alteration is located in exon 2 (coding exon 2) of the RAD23B gene. This alteration results from a C to G substitution at nucleotide position 113, causing the alanine (A) at amino acid position 38 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.99	.;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.093
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.061	.;B;.
Vest4		0.33
MutPred		0.31		Gain of ubiquitination at K34 (P = 0.078);Gain of ubiquitination at K34 (P = 0.078);.;
MVP		0.40
MPC		0.45
ClinPred		0.43	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.31

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

Other links and lift over

dbSNP: rs1244948800; hg19: chr9-110062468;