19-6002836-C-G

Variant names:

• chr19-6002836-C-G
• rs763279781
• NM_000635.4:c.1535G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000635.4(RFX2):​c.1535G>C​(p.Arg512Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFX2 NM_000635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

RFX2 (HGNC:9983): (regulatory factor X2) This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X3, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. This protein can bind to cis elements in the promoter of the IL-5 receptor alpha gene. Two transcript variants encoding different isoforms have been described for this gene, and both variants utilize alternative polyadenylation sites. [provided by RefSeq, Jul 2008]

RANBP3-DT (HGNC:55312): (RANBP3 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000635.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	NM_000635.4	MANE Select	c.1535G>C	p.Arg512Pro	missense	Exon 14 of 18	NP_000626.2
	RFX2	NM_134433.3		c.1460G>C	p.Arg487Pro	missense	Exon 13 of 17	NP_602309.1	P48378-2
	RANBP3-DT	NR_046376.1		n.113-9284C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	ENST00000303657.10	TSL:1 MANE Select	c.1535G>C	p.Arg512Pro	missense	Exon 14 of 18	ENSP00000306335.4	P48378-1
	RFX2	ENST00000359161.7	TSL:1	c.1535G>C	p.Arg512Pro	missense	Exon 14 of 18	ENSP00000352076.3	P48378-1
	RFX2	ENST00000926861.1		c.1535G>C	p.Arg512Pro	missense	Exon 14 of 18	ENSP00000596920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.60		Loss of MoRF binding (P = 7e-04)
MVP		0.54
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.94
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs763279781; hg19: chr19-6002847;