rs794727560

Variant names:

• chr5-128332983-C-T
• rs794727560
• NM_001999.4:c.4151G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

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 Pathogenic (★★). 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 18 ACMG points.

• PM1: In a domain EGF-like 22; calcium-binding (size 40) in uniprot entity FBN2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) 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.
• 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 [Pathogenic]. Clinvar id is 196780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4151G>A	p.Cys1384Tyr	missense_variant	Exon 32 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3998G>A	p.Cys1333Tyr	missense_variant	Exon 31 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4151G>A	p.Cys1384Tyr	missense_variant	Exon 32 of 65	1	NM_001999.4	ENSP00000262464.4

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

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). 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. ClinVar contains an entry for this variant (Variation ID: 196780). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (PMID: 19006240, 31316167). This variant is not present in population databases (gnomAD no frequency). 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). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Dec 03, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;.;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.0020	.;.;.;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;