chr5-128286799-T-C

Position:

chr5-128286799-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001999.4(FBN2):c.6931A>G(p.Met2311Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,694 control chromosomes in the GnomAD database, including 12,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2077 hom., cov: 33)

Exomes 𝑓: 0.071 ( 10631 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.82

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 Benign. Variant got -19 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=1.4686584E-4).

BP6

Variant 5-128286799-T-C is Benign according to our data. Variant chr5-128286799-T-C is described in ClinVar as [Benign]. Clinvar id is 129046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128286799-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.6931A>G	p.Met2311Val	missense_variant	55/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.6778A>G	p.Met2260Val	missense_variant	54/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.6931A>G	p.Met2311Val	missense_variant	55/65	1	NM_001999.4	P1	P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.3715A>G		non_coding_transcript_exon_variant	30/38

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17723

AN:

152100

Hom.:

2074

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0674

Gnomad ASJ

AF:

0.0516

Gnomad EAS

AF:

0.602

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0499

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0456

Gnomad OTH

AF:

0.0875

GnomAD3 exomes

AF:

0.112

AC:

28018

AN:

251276

Hom.:

4642

AF XY:

0.109

AC XY:

14771

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.0409

Gnomad ASJ exome

AF:

0.0564

Gnomad EAS exome

AF:

0.630

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.0525

Gnomad NFE exome

AF:

0.0453

Gnomad OTH exome

AF:

0.0722

GnomAD4 exome

AF:

0.0707

AC:

103374

AN:

1461476

Hom.:

10631

Cov.:

AF XY:

0.0718

AC XY:

52216

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.0418

Gnomad4 ASJ exome

AF:

0.0579

Gnomad4 EAS exome

AF:

0.602

Gnomad4 SAS exome

AF:

0.136

Gnomad4 FIN exome

AF:

0.0514

Gnomad4 NFE exome

AF:

0.0442

Gnomad4 OTH exome

AF:

0.0839

GnomAD4 genome

AF:

0.117

AC:

17748

AN:

152218

Hom.:

2077

Cov.:

AF XY:

0.121

AC XY:

9022

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.214

Gnomad4 AMR

AF:

0.0671

Gnomad4 ASJ

AF:

0.0516

Gnomad4 EAS

AF:

0.602

Gnomad4 SAS

AF:

0.150

Gnomad4 FIN

AF:

0.0499

Gnomad4 NFE

AF:

0.0456

Gnomad4 OTH

AF:

0.0899

Alfa

AF:

0.0618

Hom.:

1649

Bravo

AF:

0.122

TwinsUK

AF:

0.0507

AC:

188

ALSPAC

AF:

0.0410

AC:

158

ESP6500AA

AF:

0.207

AC:

914

ESP6500EA

AF:

0.0416

AC:

358

ExAC

AF:

0.115

AC:

13976

Asia WGS

AF:

0.313

AC:

1088

AN:

3478

EpiCase

AF:

0.0411

EpiControl

AF:

0.0442

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Met2311Val in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 20.7% (914/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs32209). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.6931A>G (p.Met2311Val) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.1151322 (13966/121304 control chromosomes [2250 homozygotes]), which is approximately 92106 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Congenital contractural arachnodactyly

Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.068

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.64

T;.;.

MetaRNN

Benign

0.00015

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.70

N;.;N

MutationTaster

Benign

0.10

P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.45

N;.;N

REVEL

Benign

0.28

Sift

Benign

0.43

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.13

MPC

0.24

ClinPred

0.017

GERP RS

5.3

Varity_R

0.085

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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