chr5-128408776-G-A

Position:

chr5-128408776-G-A

Variant summary

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

The ENST00000262464.9(FBN2):c.976C>T(p.Pro326Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00975 in 1,613,824 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 6 hom., cov: 32)

Exomes 𝑓: 0.010 ( 123 hom. )

Consequence

FBN2
ENST00000262464.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 4.35

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=0.010052532).

BP6

Variant 5-128408776-G-A is Benign according to our data. Variant chr5-128408776-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128408776-G-A is described in Lovd as [Benign]. Variant chr5-128408776-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00645 (982/152198) while in subpopulation NFE AF= 0.0101 (686/68004). AF 95% confidence interval is 0.00946. There are 6 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 982 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.976C>T	p.Pro326Ser	missense_variant	8/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.976C>T	p.Pro326Ser	missense_variant	8/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.976C>T	p.Pro326Ser	missense_variant	8/65	1	NM_001999.4	ENSP00000262464	P1	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.877C>T	p.Pro293Ser	missense_variant	7/33	2		ENSP00000425596
FBN2	ENST00000508053.6 linkuse as main transcript	c.976C>T	p.Pro326Ser	missense_variant	14/15	5		ENSP00000424571
FBN2	ENST00000703787.1 linkuse as main transcript	n.683C>T		non_coding_transcript_exon_variant	7/10

Frequencies

GnomAD3 genomes

AF:

0.00646

AC:

983

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00441

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00670

AC:

1683

AN:

251020

Hom.:

AF XY:

0.00671

AC XY:

910

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00438

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.00982

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.0101

AC:

14757

AN:

1461626

Hom.:

123

Cov.:

AF XY:

0.00992

AC XY:

7213

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.00503

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00425

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0113

GnomAD4 genome

AF:

0.00645

AC:

982

AN:

152198

Hom.:

Cov.:

AF XY:

0.00617

AC XY:

459

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00974

Hom.:

Bravo

AF:

0.00674

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00656

AC:

796

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FBN2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 18767143, 20981092, 27884173, 27007659, 31316167) -
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.976C>T (p.Pro326Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC, in 796/121328 control chromosomes (6 homozygotes) at a frequency of 0.0065607, which is approximately 140 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 12, 2023	- -

Congenital contractural arachnodactyly

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 25, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 12, 2017	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Connective tissue disorder

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 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 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.;D;D

Eigen

Benign

0.012

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;.;.;T

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Uncertain

0.0025

MutationAssessor

Benign

1.4

L;.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.2

D;.;D;D

REVEL

Uncertain

0.43

Sift

Benign

0.10

T;.;T;T

Sift4G

Benign

0.085

.;.;.;T

Polyphen

0.074

B;.;B;B

Vest4

0.21

MVP

0.61

MPC

0.35

ClinPred

0.031

GERP RS

3.9

Varity_R

0.22

gMVP

0.52

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