rs1045107391

Positions:

chr5-128286736-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The ENST00000262464.9(FBN2):c.6994G>A(p.Asp2332Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D2332D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.21

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 -4 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.361826).

BS2

High AC in GnomAdExome4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.6994G>A	p.Asp2332Asn	missense_variant	55/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.6841G>A	p.Asp2281Asn	missense_variant	54/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.6994G>A	p.Asp2332Asn	missense_variant	55/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.3778G>A		non_coding_transcript_exon_variant	30/38

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251370

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135846

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727202

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:

0.0000468

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2023	The FBN2 c.6994G>A; p.Asp2332Asn variant (rs886059894), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 350765). This variant is observed in the general population with an overall allele frequency of 0.002% (5/282780 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.354). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2023	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); This variant is associated with the following publications: (PMID: 19006240, 18767143) -

Congenital contractural arachnodactyly

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

The p.D2332N variant (also known as c.6994G>A), located in coding exon 55 of the FBN2 gene, results from a G to A substitution at nucleotide position 6994. The aspartic acid at codon 2332 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;.;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

0.60

N;.;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

N;.;N

REVEL

Uncertain

0.35

Sift

Benign

0.19

T;.;T

Polyphen

1.0

D;.;D

Vest4

0.23

MutPred

0.71

Gain of catalytic residue at D2332 (P = 0.2502);.;Gain of catalytic residue at D2332 (P = 0.2502);

MVP

0.63

MPC

0.36

ClinPred

0.71

GERP RS

5.3

Varity_R

0.097

gMVP

0.86

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