chr5-128377867-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_001999.4(FBN2):c.1734G>C(p.Glu578Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.659

Publications

5 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 -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

BP6

Variant 5-128377867-C-G is Benign according to our data. Variant chr5-128377867-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458736.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000842 (123/1461036) while in subpopulation MID AF = 0.00174 (10/5762). AF 95% confidence interval is 0.000941. There are 0 homozygotes in GnomAdExome4. There are 67 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.1734G>C	p.Glu578Asp	missense_variant	Exon 13 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.1581G>C	p.Glu527Asp	missense_variant	Exon 12 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.1734G>C	p.Glu578Asp	missense_variant	Exon 13 of 65	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000508989.5 link	c.1635G>C	p.Glu545Asp	missense_variant	Exon 12 of 33	2		ENSP00000425596.1	D6RJI3
FBN2	ENST00000511489.1 link	n.-46G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152130

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

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

251010

AF XY:

0.0000663

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000842

AC:

123

AN:

1461036

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726864

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33436

American (AMR)

AF:

0.0000448

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000104

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000792

AC:

AN:

1111376

Other (OTH)

AF:

0.000133

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000113

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E578D variant (also known as c.1734G>C), located in coding exon 13 of the FBN2 gene, results from a G to C substitution at nucleotide position 1734. The glutamic acid at codon 578 is replaced by aspartic acid, 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 deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome

Uncertain:1

Jun 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 23, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2 related disorders (Frederic et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 458736; Landrum et al., 2016) -

not specified

Benign:1

Dec 11, 2023

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.1734G>C (p.Glu578Asp) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251010 control chromosomes. The observed variant frequency is approximately 38 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1734G>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Congenital contractural arachnodactyly

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;D;D

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;.;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;M;.

PhyloP100

0.66

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

D;.;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0050

D;.;D;D

Sift4G

Uncertain

0.020

.;.;.;D

Polyphen

0.98

D;.;D;D

Vest4

0.68

MutPred

0.85

Gain of relative solvent accessibility (P = 0.1066);.;Gain of relative solvent accessibility (P = 0.1066);.;

MVP

0.89

MPC

0.82

ClinPred

0.76

GERP RS

1.4

Varity_R

0.48

gMVP

0.89

Mutation Taster

=72/28

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

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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