rs1060503503

chr5-128259692-A-AT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001999.4(FBN2):c.8501_8502insA(p.Tyr2834Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. 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: FBN2 NM_001999.4 stop_gained, frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0272 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.8501_8502insA	p.Tyr2834Ter	stop_gained, frameshift_variant	65/65	ENST00000262464.9
FBN2	XM_017009228.3	c.8348_8349insA	p.Tyr2783Ter	stop_gained, frameshift_variant	64/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.8501_8502insA	p.Tyr2834Ter	stop_gained, frameshift_variant	65/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 16, 2017

This sequence change inserts one nucleotide in exon 65 of the FBN2 mRNA (c.8501dupA), causing a frameshift at codon 2834. This creates a premature translational stop signal in the last exon of the FBN2 mRNA (p.Tyr2834*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 79 amino acids of the FBN2 protein. Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 79 of the FBN2 protein are critical for its function. In summary, this is a novel truncation with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a FBN2-related disease. -

Computational scores

Source: dbNSFP v4.3

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: rs1060503503; hg19: chr5-127595384;