Genetic Variant RBFOX2:c.1138-16C>A (chr22-35746577-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001349999.2(RBFOX2):c.1138-16C>A variant causes a intron change. The variant allele was found at a frequency of 0.00000221 in 1,357,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

RBFOX2
NM_001349999.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.76

Publications

0 publications found

Variant links:

Genes affected

RBFOX2 (HGNC:9906): (RNA binding fox-1 homolog 2) This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RBFOX2 Gene-Disease associations (from GenCC):

congenital heart defects, multiple types
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
congenital heart disease
Inheritance: AD Classification: STRONG Submitted by: ClinGen

RBFOX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.18).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349999.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RBFOX2	NM_001349999.2	MANE Select	c.1138-16C>A	intron	N/A	NP_001336928.2	A0A8Q3WKT3
RBFOX2	NM_001082578.4		c.1150-16C>A	intron	N/A	NP_001076047.2	O43251-8
RBFOX2	NM_001082579.3		c.1147-16C>A	intron	N/A	NP_001076048.2	O43251-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RBFOX2	ENST00000695854.1	MANE Select	c.1138-16C>A	intron	N/A	ENSP00000512219.1	A0A8Q3WKT3
RBFOX2	ENST00000438146.7	TSL:1	c.1150-16C>A	intron	N/A	ENSP00000413035.2	O43251-8
RBFOX2	ENST00000449924.6	TSL:1	c.937-16C>A	intron	N/A	ENSP00000391670.2	O43251-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000544

AC:

AN:

183960

AF XY:

0.0000100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000221

AC:

AN:

1357706

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

671684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30068

American (AMR)

AF:

0.00

AC:

AN:

33586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23142

East Asian (EAS)

AF:

0.00

AC:

AN:

36718

South Asian (SAS)

AF:

0.0000130

AC:

AN:

76652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5440

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1044162

Other (OTH)

AF:

0.00

AC:

AN:

56076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

6.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over