5-128330606-C-T

Position:

chr5-128330606-C-T

Variant summary

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

The NM_001999.4(FBN2):c.4312G>A(p.Glu1438Lys) variant causes a missense change. The variant allele was found at a frequency of 0.01 in 1,614,008 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 5 hom., cov: 33)

Exomes 𝑓: 0.010 ( 123 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.96

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=0.018452108).

BP6

Variant 5-128330606-C-T is Benign according to our data. Variant chr5-128330606-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128330606-C-T is described in Lovd as [Likely_benign]. Variant chr5-128330606-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1239/152268) while in subpopulation NFE AF= 0.012 (817/68020). AF 95% confidence interval is 0.0113. There are 5 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.4312G>A	p.Glu1438Lys	missense_variant	33/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.4159G>A	p.Glu1387Lys	missense_variant	32/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.4312G>A	p.Glu1438Lys	missense_variant	33/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

1239

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.00801

AC:

2013

AN:

251322

Hom.:

AF XY:

0.00833

AC XY:

1131

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00218

Gnomad SAS exome

AF:

0.00578

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00913

GnomAD4 exome

AF:

0.0102

AC:

14954

AN:

1461740

Hom.:

123

Cov.:

AF XY:

0.0104

AC XY:

7532

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00472

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.00118

Gnomad4 SAS exome

AF:

0.00614

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.00969

GnomAD4 genome

AF:

0.00814

AC:

1239

AN:

152268

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

616

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00752

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0142

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.00751

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0112

AC:

ExAC

AF:

0.00795

AC:

965

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FBN2: BS1, BS2 -
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.4312G>A (p.Glu1438Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 964/121286 control chromosomes (10 homozygotes) at a frequency of 0.0079482, which is approximately 170 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000469), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Glu1438Lys in exon 33 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 1.1% (96/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs56168072). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2013	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	Genetic Services Laboratory, University of Chicago	May 23, 2014	- -

Congenital contractural arachnodactyly

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 27, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2014

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

May 27, 2022

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;D;D;D

Eigen

Benign

-0.020

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.;.;D;D

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.3

L;.;L;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;.;N;D;N

REVEL

Uncertain

0.48

Sift

Benign

0.076

T;.;T;T;T

Sift4G

Benign

0.83

.;.;.;T;T

Polyphen

0.34

B;.;B;.;P

Vest4

0.74

MVP

0.45

MPC

0.43

ClinPred

0.017

GERP RS

4.2

Varity_R

0.17

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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