22-35746483-AAGCGGCTGC-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -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 id is 3636250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX2	NM_001349999.2	c.1207_1215delGCAGCCGCT	p.Ala403_Ala405del	conservative_inframe_deletion	Exon 12 of 14	ENST00000695854.1	NP_001336928.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX2	ENST00000695854.1	c.1207_1215delGCAGCCGCT	p.Ala403_Ala405del	conservative_inframe_deletion	Exon 12 of 14		NM_001349999.2	ENSP00000512219.1
RBFOX2	ENST00000438146.7	c.1219_1227delGCAGCCGCT	p.Ala407_Ala409del	conservative_inframe_deletion	Exon 12 of 14	1		ENSP00000413035.2
RBFOX2	ENST00000449924.6	c.1006_1014delGCAGCCGCT	p.Ala336_Ala338del	conservative_inframe_deletion	Exon 11 of 13	1		ENSP00000391670.2
RBFOX2	ENST00000414461.6	c.966_974delGCAGCCGCT	p.Gln323_Leu325del	disruptive_inframe_deletion	Exon 10 of 12	1		ENSP00000407855.2
RBFOX2	ENST00000695805.1	n.*500_*508delGCAGCCGCT		non_coding_transcript_exon_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4190_*4198delGCAGCCGCT		non_coding_transcript_exon_variant	Exon 13 of 15			ENSP00000512187.1
RBFOX2	ENST00000695805.1	n.*500_*508delGCAGCCGCT		3_prime_UTR_variant	Exon 11 of 13			ENSP00000512185.1
RBFOX2	ENST00000695807.1	n.*4190_*4198delGCAGCCGCT		3_prime_UTR_variant	Exon 13 of 15			ENSP00000512187.1

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

GnomAD3 exomes AF: 0.00109 AC: 264 AN: 242488 Hom.: 0 AF XY: 0.00102 AC XY: 134 AN XY: 131460

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 SAS exome AF: 0.000369

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

Gnomad4 AFR exome AF: 0.000879

Gnomad4 AMR exome AF: 0.000529

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000941

Gnomad4 SAS exome AF: 0.000563

Gnomad4 FIN exome AF: 0.00602

Gnomad4 NFE exome AF: 0.000426

Gnomad4 OTH exome AF: 0.000684

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

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000521

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749060025; hg19: chr22-36142530;