5-128339011-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001999.4(FBN2):c.3394G>A(p.Val1132Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000288 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1132V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 5.06

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

congenital contractural arachnodactyly
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
carpal tunnel syndrome
Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
macular degeneration, early-onset
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 5-128339011-C-T is Benign according to our data. Variant chr5-128339011-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213228.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000197 (30/152170) while in subpopulation NFE AF = 0.000338 (23/68032). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.3394G>A	p.Val1132Ile	missense_variant	Exon 26 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.3241G>A	p.Val1081Ile	missense_variant	Exon 25 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.3394G>A	p.Val1132Ile	missense_variant	Exon 26 of 65	1	NM_001999.4	ENSP00000262464.4		P35556-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251394

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000298

AC:

435

AN:

1461624

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00139

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000323

AC:

359

AN:

1111780

Other (OTH)

AF:

0.000248

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41442

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FBN2 c.3394G>A; p.Val1132Ile variant (rs138834515) is reported in the literature in a family affected with adolescent idiopathic scoliosis, although it was not demonstrated to be causative (Jiang 2020). This variant is found in the general population with an overall allele frequency of 0.02% (48/282800 alleles) in the Genome Aggregation Database. The valine at codon 1132 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.431). However, due to limited information, the clinical significance of the p.Val1132Ile variant is uncertain at this time. References: Jiang et al. Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis. J Med Genet. 2020 Jun;57(6):405-413. PMID: 32381728. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24205039, 32381728) -

Congenital contractural arachnodactyly

Uncertain:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

May 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V1132I variant (also known as c.3394G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3394. The valine at codon 1132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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. -

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

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FBN2 NM_001999.3 exon 26 p.Val1132Ile (c.3394G>A): This variant has not been reported in the literature and is present in 0.03% (7/19946) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-127674703-C-T). This variant is present in ClinVar (Variation ID:213228). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

Aug 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FBN2 c.3394G>A (p.Val1132Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251394 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Congenital Contractural Arachnodactyly phenotype (4.7e-05). c.3394G>A has been reported in the literature in a family with at least one individual affected with adolescent idiopathic scoliosis, without strong evidence for causality (Jiang_2020). This report does not provide unequivocal conclusions about association of the variant with Congenital Contractural Arachnodactyly. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32381728). ClinVar contains an entry for this variant (Variation ID: 213228). Based on the evidence outlined above, the variant was classified as likely benign. -

Connective tissue disorder

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;T;T

Eigen

Benign

0.093

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;.;.;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.10

N;.;N;.

PhyloP100

5.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.82

N;.;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.041

D;.;D;T

Sift4G

Benign

0.20

.;.;.;T

Polyphen

0.054

B;.;B;P

Vest4

0.41

MVP

0.70

MPC

0.31

ClinPred

0.040

GERP RS

5.1

PromoterAI

-0.053

Neutral

(source)

Varity_R

0.13

gMVP

0.46

Mutation Taster

=227/73

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over