chr5-128301424-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001999.4(FBN2):c.6004A>G(p.Asn2002Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.296

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.41223568).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.6004A>G	p.Asn2002Asp	missense_variant	Exon 47 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.5851A>G	p.Asn1951Asp	missense_variant	Exon 46 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.6004A>G	p.Asn2002Asp	missense_variant	Exon 47 of 65	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000703783.1 link	n.2788A>G		non_coding_transcript_exon_variant	Exon 22 of 38
FBN2	ENST00000703785.1 link	n.2707A>G		non_coding_transcript_exon_variant	Exon 21 of 27

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152206

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251246

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135784

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:

0.0000226

AC:

AN:

1461202

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

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:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000202

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Uncertain:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2002 of the FBN2 protein (p.Asn2002Asp). This variant is present in population databases (rs773305589, gnomAD 0.003%). This missense change has been observed in individual(s) with aortic root dilation (internal data). ClinVar contains an entry for this variant (Variation ID: 213343). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBN2 protein function with a negative predictive value of 80%. 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. -

Oct 26, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (A>G) at position 6004 of the coding sequence of the FBN2 gene that results in an asparagine to aspartic acid amino acid change at residue 2002 of the fibrillin 2 protein. This residue falls in the calcium binding EGF-like 33 domain which interacts with MFAP4 (Uniprot). This is a previously reported variant (ClinVar 213343) that has not been observed in individuals affected by a FBN2-related disorder in the published literature, to our knowledge. This variant is present in 10 of 403452 alleles (0.0025%) in the gnomAD population dataset. Multiple bioinformatic tools provide conflicting predictions concerning this asparagine to aspartic acid amino acid change, and the Asn2002 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2 -

FBN2-related disorder

Uncertain:1

Jan 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN2 c.6004A>G variant is predicted to result in the amino acid substitution p.Asn2002Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-127637116-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Oct 08, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N2002D variant (also known as c.6004A>G), located in coding exon 47 of the FBN2 gene, results from an A to G substitution at nucleotide position 6004. The asparagine at codon 2002 is replaced by aspartic acid, an amino acid with highly similar properties, and is located in the cbEGF-like #30 domain. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jun 26, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asn2002Asp (AAC>GAC): c.6004 A>G in exon 47 of the FBN2 gene (NM_001999.3) The N2002D variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The N2002D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N2002D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Moreover, no missense mutations in nearby residues have been reported in association with CCA, indicating that this region of the protein may be tolerant to change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;T

Eigen

Benign

0.027

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

T;.;.

M_CAP

Benign

0.067

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

0.94

L;.;L

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.4

N;.;N

REVEL

Uncertain

0.34

Sift

Benign

0.38

T;.;T

Polyphen

0.80

P;.;P

Vest4

0.34

MutPred

0.49

Loss of ubiquitination at K1998 (P = 0.1473);.;Loss of ubiquitination at K1998 (P = 0.1473);

MVP

0.73

MPC

0.41

ClinPred

0.42

GERP RS

5.5

Varity_R

0.16

gMVP

0.65

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

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