rs794727560

chr5-128332983-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001999.4(FBN2):c.4151G>A(p.Cys1384Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1384F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.91

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain 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 where missense usually causes diseases, FBN2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 5-128332983-C-T is Pathogenic according to our data. Variant chr5-128332983-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196780.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4151G>A	p.Cys1384Tyr	missense_variant	32/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3998G>A	p.Cys1333Tyr	missense_variant	31/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4151G>A	p.Cys1384Tyr	missense_variant	32/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1384 of the FBN2 protein (p.Cys1384Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (PMID: 19006240, 31316167). ClinVar contains an entry for this variant (Variation ID: 196780). 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 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). This variant disrupts the p.Cys1384 amino acid residue in FBN2. Other variant(s) that disrupt this residue have been observed in individuals with FBN2-related conditions (PMID: 19006240, 31316167), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 03, 2014

- -

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	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.2	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;.;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.99
MutPred		1.0		Gain of phosphorylation at C1384 (P = 0.0693);.;Gain of phosphorylation at C1384 (P = 0.0693);.;.;
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.99

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: rs794727560; hg19: chr5-127668675;