5-128286782-G-T

Position:

chr5-128286782-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001999.4(FBN2):c.6948C>A(p.Ile2316Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,916 control chromosomes in the GnomAD database, including 385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 21 hom., cov: 33)

Exomes 𝑓: 0.019 ( 364 hom. )

Consequence

FBN2
NM_001999.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.13

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:

FBN2 (HGNC:):

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 5-128286782-G-T is Benign according to our data. Variant chr5-128286782-G-T is described in ClinVar as [Benign]. Clinvar id is 129047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128286782-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0149 (2274/152320) while in subpopulation SAS AF= 0.0255 (123/4828). AF 95% confidence interval is 0.0218. There are 21 homozygotes in gnomad4. There are 1119 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2274 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.6948C>A	p.Ile2316Ile	synonymous_variant	55/65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 linkuse as main transcript	c.6795C>A	p.Ile2265Ile	synonymous_variant	54/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.6948C>A	p.Ile2316Ile	synonymous_variant	55/65	1	NM_001999.4	ENSP00000262464.4		P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.3732C>A		non_coding_transcript_exon_variant	30/38

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2273

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0252

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0180

AC:

4521

AN:

251312

Hom.:

AF XY:

0.0192

AC XY:

2602

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00899

Gnomad ASJ exome

AF:

0.0137

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0316

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0215

Gnomad OTH exome

AF:

0.0238

GnomAD4 exome

AF:

0.0189

AC:

27681

AN:

1461596

Hom.:

364

Cov.:

AF XY:

0.0195

AC XY:

14153

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.00964

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0318

Gnomad4 FIN exome

AF:

0.0226

Gnomad4 NFE exome

AF:

0.0194

Gnomad4 OTH exome

AF:

0.0180

GnomAD4 genome

AF:

0.0149

AC:

2274

AN:

152320

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1119

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0255

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.0218

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0132

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0195

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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	Ile2316Ile in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.0% (169/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17608368). -

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.6948C>A (p.Ile2316Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate an SRp40 ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0185658 (2252/121298 control chromosomes [40 homozygotes]), which is approximately 14853 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. 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. -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 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

Jul 05, 2022

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.12

DANN

Benign

0.65

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