rs749060025

Variant names:

• chr22-35746483-AAGCGGCTGC-A
• rs749060025
• NM_001349999.2:c.1207_1215delGCAGCCGCT

Your query was ambiguous. Multiple possible variants found:

• chr22-35746483-AAGCGGCTGC-A
• chr22-35746483-AAGCGGCTGC-AAGCGGCTGCAGCGGCTGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_001349999.2(RBFOX2):​c.1207_1215delGCAGCCGCT​(p.Ala403_Ala405del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00069 in 1,603,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: RBFOX2 NM_001349999.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.15
• 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 -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001349999.2.
• BP6: Variant 22-35746483-AAGCGGCTGC-A is Benign according to our data. Variant chr22-35746483-AAGCGGCTGC-A is described in ClinVar as Benign. ClinVar VariationId is 3636250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 124 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.1207_1215delGCAGCCGCT	p.Ala403_Ala405del	conservative_inframe_deletion	Exon 12 of 14	NP_001336928.2	A0A8Q3WKT3
	RBFOX2	NM_001082578.4		c.1219_1227delGCAGCCGCT	p.Ala407_Ala409del	conservative_inframe_deletion	Exon 12 of 14	NP_001076047.2	O43251-8
	RBFOX2	NM_001082579.3		c.1216_1224delGCAGCCGCT	p.Ala406_Ala408del	conservative_inframe_deletion	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.1207_1215delGCAGCCGCT	p.Ala403_Ala405del	conservative_inframe_deletion	Exon 12 of 14	ENSP00000512219.1	A0A8Q3WKT3
	RBFOX2	ENST00000438146.7	TSL:1	c.1219_1227delGCAGCCGCT	p.Ala407_Ala409del	conservative_inframe_deletion	Exon 12 of 14	ENSP00000413035.2	O43251-8
	RBFOX2	ENST00000449924.6	TSL:1	c.1006_1014delGCAGCCGCT	p.Ala336_Ala338del	conservative_inframe_deletion	Exon 11 of 13	ENSP00000391670.2	O43251-10

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00109 AC: 264 AN: 242488 AF XY: 0.00102

Gnomad AFR exome AF: 0.000952

Gnomad AMR exome AF: 0.000630

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00678

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000677 AC: 982 AN: 1450880 Hom.: 0 AF XY: 0.000651 AC XY: 470 AN XY: 722140

African (AFR) AF: 0.000879 AC: 29 AN: 33000

American (AMR) AF: 0.000529 AC: 23 AN: 43508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.000941 AC: 37 AN: 39312

South Asian (SAS) AF: 0.000563 AC: 48 AN: 85286

European-Finnish (FIN) AF: 0.00602 AC: 321 AN: 53322

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5730

European-Non Finnish (NFE) AF: 0.000426 AC: 471 AN: 1104960

Other (OTH) AF: 0.000684 AC: 41 AN: 59924

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000993 AC XY: 74 AN XY: 74506

African (AFR) AF: 0.000673 AC: 28 AN: 41582

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000521

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=44/156	disease causing

Splicing

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

Other links and lift over

dbSNP: rs749060025; hg19: chr22-36142530;