Genetic Variant RFX2:p.Arg702Leu (chr19-5994902-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000635.4(RFX2):c.2105G>T(p.Arg702Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,609,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R702H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

RFX2
NM_000635.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.139

Publications

0 publications found

Variant links:

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]

RFX2 links:

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

RANBP3-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063965023).

BS2

High AC in GnomAd4 at 66 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX2	NM_000635.4	MANE Select	c.2105G>T	p.Arg702Leu	missense	Exon 18 of 18	NP_000626.2
RFX2	NM_134433.3		c.2030G>T	p.Arg677Leu	missense	Exon 17 of 17	NP_602309.1	P48378-2
RANBP3-DT	NR_046376.1		n.112+16388C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX2	ENST00000303657.10	TSL:1 MANE Select	c.2105G>T	p.Arg702Leu	missense	Exon 18 of 18	ENSP00000306335.4	P48378-1
RFX2	ENST00000359161.7	TSL:1	c.2105G>T	p.Arg702Leu	missense	Exon 18 of 18	ENSP00000352076.3	P48378-1
RFX2	ENST00000926861.1		c.2126G>T	p.Arg709Leu	missense	Exon 18 of 18	ENSP00000596920.1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000139

AC:

AN:

244210

AF XY:

0.0000752

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000515

AC:

AN:

1457608

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

725464

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33474

American (AMR)

AF:

0.000134

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49412

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111860

Other (OTH)

AF:

0.000149

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000433

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41586

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000500

Hom.:

Bravo

AF:

0.000548

ExAC

AF:

0.000173

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

3.3

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.045

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.69

M_CAP

Benign

0.060

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PhyloP100

0.14

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.24

Sift4G

Benign

0.30

Polyphen

0.021

Vest4

0.23

MVP

0.26

MPC

1.1

ClinPred

0.016

GERP RS

-6.1

Varity_R

0.058

gMVP

0.39

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over