chr22-35746474-C-A

Variant names:

• chr22-35746474-C-A
• rs370030634
• NM_001349999.2:c.1225G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001349999.2(RBFOX2):​c.1225G>T​(p.Gly409Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000152 in 1,444,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G409S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 missense, splice_region
• Scores: Splicing: ADA: 0.9933
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 22 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX2	NM_001349999.2	MANE Select	c.1225G>T	p.Gly409Cys	missense splice_region	Exon 12 of 14	NP_001336928.2	A0A8Q3WKT3
	RBFOX2	NM_001082578.4		c.1237G>T	p.Gly413Cys	missense splice_region	Exon 12 of 14	NP_001076047.2	O43251-8
	RBFOX2	NM_001082579.3		c.1234G>T	p.Gly412Cys	missense splice_region	Exon 12 of 14	NP_001076048.2	O43251-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX2	ENST00000695854.1	MANE Select	c.1225G>T	p.Gly409Cys	missense splice_region	Exon 12 of 14	ENSP00000512219.1	A0A8Q3WKT3
	RBFOX2	ENST00000438146.7	TSL:1	c.1237G>T	p.Gly413Cys	missense splice_region	Exon 12 of 14	ENSP00000413035.2	O43251-8
	RBFOX2	ENST00000449924.6	TSL:1	c.1024G>T	p.Gly342Cys	missense splice_region	Exon 11 of 13	ENSP00000391670.2	O43251-10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 239732 AF XY: 0.00

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: 0.0000152 AC: 22 AN: 1444060 Hom.: 0 Cov.: 30 AF XY: 0.0000181 AC XY: 13 AN XY: 718760

African (AFR) AF: 0.00 AC: 0 AN: 32812

American (AMR) AF: 0.00 AC: 0 AN: 42950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 84596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000191 AC: 21 AN: 1100312

Other (OTH) AF: 0.0000168 AC: 1 AN: 59640

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.27	T
PhyloP100		4.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.64		Loss of disorder (P = 0.0325)
MVP		0.47
MPC		2.2
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.84
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
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: rs370030634; hg19: chr22-36142521;