rs1554122857

Positions:

• chr5-128335566-A-C
• chr5-128335566-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001999.4(FBN2):​c.3736T>G​(p.Cys1246Gly) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1246F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain EGF-like 19; calcium-binding (size 40) in uniprot entity FBN2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001999.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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
• PP5: Variant 5-128335566-A-C is Pathogenic according to our data. Variant chr5-128335566-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1459134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3736T>G	p.Cys1246Gly	missense_variant	29/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3583T>G	p.Cys1195Gly	missense_variant	28/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3736T>G	p.Cys1246Gly	missense_variant	29/65	1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The p.C1246G variant (also known as c.3736T>G), located in coding exon 29 of the FBN2 gene, results from a T to G substitution at nucleotide position 3736. The cysteine at codon 1246 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with concerns for congenital contractural arachnodactyly (Paulson ML et al. Int. J. Tuberc. Lung Dis., 2012 Apr;16:561-3; Meerschaut I et al. Genet Med, 2020 Jan;22:124-131). 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). Based on internal structural analysis, this alteration disrupts the formation of a structural disulfide bond in the EGF-like 19 domain of FBN2 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Congenital contractural arachnodactyly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2021

For these reasons, this variant has been classified as Pathogenic. 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN2 protein function. This missense change has been observed in individuals with clinical features of congenital contractural arachnodactyly (PMID: 22325249, 31316167; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1246 of the FBN2 protein (p.Cys1246Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D;.;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-11	D;.;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.99
MutPred		0.98		Loss of stability (P = 0.0131);.;Loss of stability (P = 0.0131);.;.;
MVP		0.99
MPC		0.30
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127671258;