rs568169177

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001999.4(FBN2):c.2406T>G(p.Asp802Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,364 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.52

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.2581818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.2406T>G	p.Asp802Glu	missense_variant	18/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.2253T>G	p.Asp751Glu	missense_variant	17/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.2406T>G	p.Asp802Glu	missense_variant	18/65	1	NM_001999.4	P1	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.2307T>G	p.Asp769Glu	missense_variant	17/33	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251192

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135782

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727022

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The p.D802E variant (also known as c.2406T>G), located in coding exon 18 of the FBN2 gene, results from a T to G substitution at nucleotide position 2406. The aspartic acid at codon 802 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 15, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces aspartic acid with glutamic acid at codon 802 of the FBN2 protein (p.Asp802Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs568169177, ExAC 0.002%). This variant has not been reported in the literature in individuals with FBN2-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;D;D

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.096

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.73

T;.;.;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

-0.041

MutationAssessor

Benign

1.9

L;.;L;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.045

D;.;D;T

Sift4G

Benign

0.18

.;.;.;T

Polyphen

0.0010

B;.;B;B

Vest4

0.28

MutPred

0.48

Gain of glycosylation at S804 (P = 0.079);.;Gain of glycosylation at S804 (P = 0.079);.;

MVP

0.78

MPC

0.23

ClinPred

0.41

GERP RS

1.9

Varity_R

0.13

gMVP

0.76

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