rs144574441

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):c.8351C>T(p.Pro2784Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,614,160 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 106 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.971

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=0.003291428).

BP6

Variant 5-128261749-G-A is Benign according to our data. Variant chr5-128261749-G-A is described in ClinVar as [Benign]. Clinvar id is 258529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128261749-G-A is described in Lovd as [Benign]. Variant chr5-128261749-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00148 (225/152336) while in subpopulation SAS AF= 0.0441 (213/4830). AF 95% confidence interval is 0.0392. There are 5 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.8351C>T	p.Pro2784Leu	missense_variant	64/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.8198C>T	p.Pro2733Leu	missense_variant	63/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.8351C>T	p.Pro2784Leu	missense_variant	64/65	1	NM_001999.4	P1	P35556-1

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152218

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:

0.000385

Gnomad SAS

AF:

0.0441

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00543

AC:

1364

AN:

251162

Hom.:

AF XY:

0.00742

AC XY:

1007

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0431

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00268

AC:

3916

AN:

1461824

Hom.:

106

Cov.:

AF XY:

0.00384

AC XY:

2793

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0418

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152336

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0441

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00625

AC:

759

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2015	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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2017	Variant summary: The FBN2 c.8351C>T (p.Pro2784Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro) and 4/5 in silico tools predict a benign outcome for this variant. This variant was found in the large control database ExAC in 759 of 121388 control chromosomes (26 homozygotes), predominantly observed in the South Asian subpopulation at a frequency of 0.04524 (747/16512). This frequency is about 36192 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -

Congenital contractural arachnodactyly

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	- -
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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2015

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

Dec 24, 2021

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.6

DANN

Benign

0.55

DEOGEN2

Benign

0.26

T;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.64

T;.;.

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

L;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.1

N;.;N

REVEL

Benign

0.12

Sift

Benign

0.30

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.22

MVP

0.25

MPC

0.24

ClinPred

0.0055

GERP RS

1.7

Varity_R

0.019

gMVP

0.32

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