NM_001349999.2:c.1181C>T

Variant names:

• chr22-35746518-G-A
• NM_001349999.2:c.1181C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349999.2(RBFOX2):​c.1181C>T​(p.Thr394Ile) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T394T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19955143).

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.1181C>T	p.Thr394Ile	missense	Exon 12 of 14	NP_001336928.2	A0A8Q3WKT3
	RBFOX2	NM_001082578.4		c.1193C>T	p.Thr398Ile	missense	Exon 12 of 14	NP_001076047.2	O43251-8
	RBFOX2	NM_001082579.3		c.1190C>T	p.Thr397Ile	missense	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.1181C>T	p.Thr394Ile	missense	Exon 12 of 14	ENSP00000512219.1	A0A8Q3WKT3
	RBFOX2	ENST00000438146.7	TSL:1	c.1193C>T	p.Thr398Ile	missense	Exon 12 of 14	ENSP00000413035.2	O43251-8
	RBFOX2	ENST00000449924.6	TSL:1	c.980C>T	p.Thr327Ile	missense	Exon 11 of 13	ENSP00000391670.2	O43251-10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	Benign	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.36	T
PhyloP100		7.5
PROVEAN	Benign	0.67	N
REVEL	Benign	0.070
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.27	T
Polyphen		0.030	B
Vest4		0.49
MutPred		0.16		Loss of loop (P = 0.0603)
MVP		0.43
ClinPred		0.86	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=58/42	polymorphism

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

hg19: chr22-36142565;