22-35761247-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001349999.2(RBFOX2):c.919C>T(p.Pro307Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBFOX2 NM_001349999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBFOX2	NM_001349999.2	c.919C>T	p.Pro307Ser	missense_variant	9/14	ENST00000695854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBFOX2	ENST00000695854.1	c.919C>T	p.Pro307Ser	missense_variant	9/14		NM_001349999.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2016

The P236S variant in the RBFOX2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P236S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P236S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P236S as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	26
Dann	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;.
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D;D;T;T;D;T;D;.
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T
Polyphen		0.58	P;B;B;B;B;B;B;B;.
Vest4		0.70
MutPred		0.43		.;.;.;.;.;Gain of glycosylation at P216 (P = 0.0562);.;.;Gain of glycosylation at P216 (P = 0.0562);
MVP		0.76
MPC		1.2
ClinPred		0.71	D
GERP RS		5.3
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518386; hg19: chr22-36157294;