rs202050092

Positions:

chr5-128344432-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP6BS2

The NM_001999.4(FBN2):c.3296G>A(p.Arg1099His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1099C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.17

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 Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in NM_001999.4

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.

BP6

Variant 5-128344432-C-T is Benign according to our data. Variant chr5-128344432-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.3296G>A	p.Arg1099His	missense_variant	25/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.3143G>A	p.Arg1048His	missense_variant	24/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.3296G>A	p.Arg1099His	missense_variant	25/65	1	NM_001999.4	P1	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.3197G>A	p.Arg1066His	missense_variant	24/33	2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000994

AC:

AN:

251428

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000138

AC:

202

AN:

1461408

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (ClinVar Variant ID# 213305; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -

Congenital contractural arachnodactyly

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Ehlers-Danlos syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 24, 2023

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2021

This alteration is classified as likely 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

0.093

BayesDel_addAF

Benign

-0.00056

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;D;D

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;.;.;D

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

0.41

N;.;N;.

MutationTaster

Benign

0.88

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;.;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0070

D;.;D;D

Sift4G

Benign

0.13

.;.;.;T

Polyphen

0.97

D;.;D;D

Vest4

0.69

MVP

0.79

MPC

0.85

ClinPred

0.68

GERP RS

4.5

Varity_R

0.30

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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