5-128361755-T-C

Position:

chr5-128361755-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP2PP3_StrongBS2

The NM_001999.4(FBN2):c.2522A>G(p.Tyr841Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.31

Variant links:

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]

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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, 0.984

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.2522A>G	p.Tyr841Cys	missense_variant	19/65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 linkuse as main transcript	c.2369A>G	p.Tyr790Cys	missense_variant	18/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.2522A>G	p.Tyr841Cys	missense_variant	19/65	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.2423A>G	p.Tyr808Cys	missense_variant	18/33	2		ENSP00000425596.1		D6RJI3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2017

A variant of uncertain significance has been identified in the FBN2 gene. The Y841C variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y841C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, the Y841C variant introduces a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009). Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity. -

Congenital contractural arachnodactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2022

ClinVar contains an entry for this variant (Variation ID: 424465). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (Invitae). This variant is present in population databases (rs762606715, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 841 of the FBN2 protein (p.Tyr841Cys). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;.;.;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;H;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.6

D;.;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.0020

.;.;.;D

Polyphen

0.99

D;.;D;D

Vest4

0.85

MutPred

0.88

Gain of disorder (P = 0.0381);.;Gain of disorder (P = 0.0381);.;

MVP

0.92

MPC

0.91

ClinPred

0.98

GERP RS

3.6

Varity_R

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over