NM_001349999.2:c.187-4597G>A

Variant names:

• chr22-35943494-C-T
• rs5750202
• NM_001349999.2:c.187-4597G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349999.2(RBFOX2):​c.187-4597G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,060 control chromosomes in the GnomAD database, including 5,766 homozygotes. 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: 𝑓 0.22 (5766 hom., cov: 32)
• Consequence: RBFOX2 NM_001349999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.187-4597G>A		intron_variant	Intron 1 of 13	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.187-4597G>A		intron_variant	Intron 1 of 13		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.187-4597G>A		intron_variant	Intron 1 of 13	1		ENSP00000413035.2
RBFOX2	ENST00000695807.1	n.-84-4597G>A		intron_variant	Intron 1 of 14			ENSP00000512187.1
RBFOX2	ENST00000408983.2	c.43-4597G>A		intron_variant	Intron 1 of 5	3		ENSP00000386177.2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33497 AN: 151942 Hom.: 5731 Cov.: 32

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.0984

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.221 AC: 33589 AN: 152060 Hom.: 5766 Cov.: 32 AF XY: 0.214 AC XY: 15886 AN XY: 74354

African (AFR) AF: 0.482 AC: 19968 AN: 41410

American (AMR) AF: 0.124 AC: 1899 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.0782 AC: 405 AN: 5180

South Asian (SAS) AF: 0.0989 AC: 476 AN: 4812

European-Finnish (FIN) AF: 0.0998 AC: 1057 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8828 AN: 67996

Other (OTH) AF: 0.184 AC: 389 AN: 2114

Alfa AF: 0.134 Hom.: 663

Bravo AF: 0.236

Asia WGS AF: 0.109 AC: 382 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.51
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs5750202; hg19: chr22-36339542;