rs1206843725

chr5-128338938-C-A

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.3467G>T(p.Cys1156Phe) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1156R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P: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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 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 chr5-128338939-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FBN2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 5-128338938-C-A is Pathogenic according to our data. Variant chr5-128338938-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 547356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3467G>T	p.Cys1156Phe	missense_variant	26/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3314G>T	p.Cys1105Phe	missense_variant	25/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3467G>T	p.Cys1156Phe	missense_variant	26/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2020	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). For these reasons, this allele has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been observed in individuals with congenital contractural arachnodactyly (PMID: 19006240, Invitae). ClinVar contains an entry for this variant (Variation ID: 547356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 1156 of the FBN2 protein (p.Cys1156Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;D;T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.9	D;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;.;D;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.96
MutPred		0.99		Loss of disorder (P = 0.0888);.;Loss of disorder (P = 0.0888);.;.;
MVP		0.95
MPC		0.43
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.97

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: rs1206843725; hg19: chr5-127674630;