rs190450

chr5-128278780-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):c.7200T>C(p.Ser2400=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,613,582 control chromosomes in the GnomAD database, including 400,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37099 hom., cov: 32)
  • Exomes 𝑓: 0.70 (363416 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.24

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-128278780-A-G is Benign according to our data. Variant chr5-128278780-A-G is described in ClinVar as [Benign]. Clinvar id is 129049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128278780-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.7200T>C	p.Ser2400=	synonymous_variant	57/65	ENST00000262464.9
FBN2	XM_017009228.3	c.7047T>C	p.Ser2349=	synonymous_variant	56/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.7200T>C	p.Ser2400=	synonymous_variant	57/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.3984T>C		non_coding_transcript_exon_variant	32/38

Frequencies

GnomAD3 genomes AF: 0.697 AC: 105817 AN: 151912 Hom.: 37062 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.726 AC: 182206 AN: 250932 Hom.: 66790 AF XY: 0.731 AC XY: 99107 AN XY: 135610

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.690

Gnomad ASJ exome AF: 0.716

Gnomad EAS exome AF: 0.877

Gnomad SAS exome AF: 0.763

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.704 AC: 1028278 AN: 1461552 Hom.: 363416 Cov.: 51 AF XY: 0.707 AC XY: 513707 AN XY: 727114

Gnomad4 AFR exome AF: 0.623

Gnomad4 AMR exome AF: 0.690

Gnomad4 ASJ exome AF: 0.721

Gnomad4 EAS exome AF: 0.872

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.780

Gnomad4 NFE exome AF: 0.692

Gnomad4 OTH exome AF: 0.697

GnomAD4 genome AF: 0.697 AC: 105904 AN: 152030 Hom.: 37099 Cov.: 32 AF XY: 0.704 AC XY: 52296 AN XY: 74316

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.865

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.776

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.682

Alfa AF: 0.701 Hom.: 87950

Bravo AF: 0.681

Asia WGS AF: 0.795 AC: 2763 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital contractural arachnodactyly Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2012	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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ser2400Ser in exon 57 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 36.8% (1621/4406) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs190450). -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Macular degeneration, early-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.6
Dann	Benign	0.80

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

Other links and lift over

dbSNP: rs190450; hg19: chr5-127614472; COSMIC: COSV52516190;