rs1060503507

Positions:

• chr5-128377757-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001999.4(FBN2):​c.1844G>T​(p.Cys615Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.1844G>T	p.Cys615Phe	missense_variant	13/65	ENST00000262464.9
FBN2	XM_017009228.3	c.1691G>T	p.Cys564Phe	missense_variant	12/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.1844G>T	p.Cys615Phe	missense_variant	13/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.1745G>T	p.Cys582Phe	missense_variant	12/33	2
FBN2	ENST00000511489.1	n.65G>T		non_coding_transcript_exon_variant	1/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2016

The p.C615F variant (also known as c.1844G>T), located in coding exon 13 of the FBN2 gene, results from a G to T substitution at nucleotide position 1844. The cysteine at codon 615 is replaced by phenylalanine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like # #06 domain. In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 24, 2019

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant affects a cysteine residue located within an epidermal growth factor (EGF)–like domain of the FBN2 protein. Cysteine residues in these domains are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN2 EGF-like domains affecting cysteine residues are overrepresented in patients with congenital contractural arachnodactyly (PMID: 18767143). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces cysteine with phenylalanine at codon 615 of the FBN2 protein (p.Cys615Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.7	H;.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-10	D;.;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0030	.;.;.;D
Polyphen		1.0	D;.;D;D
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.123);.;Loss of disorder (P = 0.123);.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.94
gMVP		1.0

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: rs1060503507; hg19: chr5-127713450;