rs2289821

Positions:

• chr15-22926124-A-C
• chr15-22926124-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014608.6(CYFIP1):​c.1234-17T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,878 control chromosomes in the GnomAD database, including 1,873 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 0.064 (659 hom., cov: 33)
  • Exomes 𝑓: 0.022 (1214 hom.)
• Consequence: CYFIP1 NM_014608.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114

Genes affected

CYFIP1 (HGNC:13759): (cytoplasmic FMR1 interacting protein 1) This gene encodes a protein that regulates cytoskeletal dynamics and protein translation. The encoded protein is a component of the WAVE regulatory complex (WRC), which promotes actin polymerization. This protein also interacts with the synaptic functional regulator FMR1 protein and translation initiation factor 4E to inhibit protein translation. A large chromosomal deletion including this gene is associated with increased risk of schizophrenia and epilepsy in human patients. Reduced expression of this gene has been observed in various human cancers and the encoded protein may inhibit tumor invasion. [provided by RefSeq, Mar 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYFIP1	NM_014608.6	c.1234-17T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000617928.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYFIP1	ENST00000617928.5	c.1234-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014608.6	P1
CYFIP1	ENST00000610365.4	c.1234-17T>G		splice_polypyrimidine_tract_variant, intron_variant		1		P1
CYFIP1	ENST00000612288.2	c.1234-17T>G		splice_polypyrimidine_tract_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9766 AN: 152026 Hom.: 659 Cov.: 33

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0869

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0822

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0450 AC: 11295 AN: 251216 Hom.: 565 AF XY: 0.0416 AC XY: 5648 AN XY: 135746

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.0917

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.0838

Gnomad SAS exome AF: 0.0661

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0225 AC: 32878 AN: 1461734 Hom.: 1214 Cov.: 31 AF XY: 0.0231 AC XY: 16797 AN XY: 727166

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0922

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.0842

Gnomad4 SAS exome AF: 0.0641

Gnomad4 FIN exome AF: 0.00948

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0642 AC: 9774 AN: 152144 Hom.: 659 Cov.: 33 AF XY: 0.0644 AC XY: 4793 AN XY: 74390

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0868

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.0820

Gnomad4 SAS AF: 0.0697

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0272 Hom.: 48

Bravo AF: 0.0732

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.87
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs2289821; hg19: chr15-22946944;