5-128349443-C-T

Position:

chr5-128349443-C-T

Variant summary

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

The ENST00000262464.9(FBN2):c.2893G>A(p.Val965Ile) variant causes a missense change. The variant allele was found at a frequency of 0.694 in 1,613,198 control chromosomes in the GnomAD database, including 390,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 35996 hom., cov: 32)

Exomes 𝑓: 0.69 ( 354976 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 4.11

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=3.1779655E-6).

BP6

Variant 5-128349443-C-T is Benign according to our data. Variant chr5-128349443-C-T is described in ClinVar as [Benign]. Clinvar id is 129039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128349443-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.2893G>A	p.Val965Ile	missense_variant	23/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.2740G>A	p.Val914Ile	missense_variant	22/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.2893G>A	p.Val965Ile	missense_variant	23/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.2794G>A	p.Val932Ile	missense_variant	22/33	2		ENSP00000425596

Frequencies

GnomAD3 genomes

AF:

0.686

AC:

104185

AN:

151884

Hom.:

35967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.620

Gnomad AMI

AF:

0.667

Gnomad AMR

AF:

0.748

Gnomad ASJ

AF:

0.758

Gnomad EAS

AF:

0.921

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.683

Gnomad OTH

AF:

0.696

GnomAD3 exomes

AF:

0.728

AC:

182726

AN:

250892

Hom.:

67593

AF XY:

0.725

AC XY:

98239

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.621

Gnomad AMR exome

AF:

0.819

Gnomad ASJ exome

AF:

0.771

Gnomad EAS exome

AF:

0.939

Gnomad SAS exome

AF:

0.731

Gnomad FIN exome

AF:

0.709

Gnomad NFE exome

AF:

0.682

Gnomad OTH exome

AF:

0.708

GnomAD4 exome

AF:

0.695

AC:

1015407

AN:

1461196

Hom.:

354976

Cov.:

AF XY:

0.696

AC XY:

505945

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.619

Gnomad4 AMR exome

AF:

0.810

Gnomad4 ASJ exome

AF:

0.771

Gnomad4 EAS exome

AF:

0.918

Gnomad4 SAS exome

AF:

0.733

Gnomad4 FIN exome

AF:

0.719

Gnomad4 NFE exome

AF:

0.678

Gnomad4 OTH exome

AF:

0.699

GnomAD4 genome

AF:

0.686

AC:

104264

AN:

152002

Hom.:

35996

Cov.:

AF XY:

0.690

AC XY:

51239

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.620

Gnomad4 AMR

AF:

0.748

Gnomad4 ASJ

AF:

0.758

Gnomad4 EAS

AF:

0.921

Gnomad4 SAS

AF:

0.739

Gnomad4 FIN

AF:

0.710

Gnomad4 NFE

AF:

0.683

Gnomad4 OTH

AF:

0.698

Alfa

AF:

0.689

Hom.:

88448

Bravo

AF:

0.685

TwinsUK

AF:

0.683

AC:

2531

ALSPAC

AF:

0.688

AC:

2651

ESP6500AA

AF:

0.628

AC:

2766

ESP6500EA

AF:

0.680

AC:

5846

ExAC

AF:

0.723

AC:

87775

Asia WGS

AF:

0.813

AC:

2829

AN:

3478

EpiCase

AF:

0.680

EpiControl

AF:

0.679

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2014	This is a RefSeq error. The reference base (c.2893G) is the minor allele. This a llele (G) has been identified in 32% (2754/8600) of European American chromosome s and 37% (1640/4406) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs154001) and thus meets c riteria to be classified as benign. -

not provided

Benign:2

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.2893G>A (p.Val965Ile) variant causes a missense change involving the alteration of a conserved nucleotide that 4/4 in silico tools (Mutation Taster not captured here due to low p-value) predict a benign outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 0.7233944 (87496/120952 (32094 homozygotes)), therefore, suggesting that the A allele is the major allele, the allele most commonly observed in the general population. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 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. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Macular degeneration, early-onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

T;.;.;T

MetaRNN

Benign

0.0000032

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.39

N;.;N;.

MutationTaster

Benign

0.044

P;P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.30

N;.;N;N

REVEL

Benign

0.24

Sift

Benign

0.33

T;.;T;T

Sift4G

Benign

0.44

.;.;.;T

Polyphen

0.0010

B;.;B;B

Vest4

0.20

MPC

0.21

ClinPred

0.011

GERP RS

3.3

Varity_R

0.10

gMVP

0.13

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