rs190450

Variant names:

• chr5-128278780-A-G
• rs190450
• NM_001999.4:c.7200T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.7200T>C​(p.Ser2400Ser) 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
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7200T>C	p.Ser2400Ser	synonymous_variant	Exon 57 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7047T>C	p.Ser2349Ser	synonymous_variant	Exon 56 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7200T>C	p.Ser2400Ser	synonymous_variant	Exon 57 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3984T>C		non_coding_transcript_exon_variant	Exon 32 of 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

GnomAD2 exomes AF: 0.726 AC: 182206 AN: 250932 AF XY: 0.731

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 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

African (AFR) AF: 0.623 AC: 20848 AN: 33472

American (AMR) AF: 0.690 AC: 30879 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 18850 AN: 26130

East Asian (EAS) AF: 0.872 AC: 34591 AN: 39682

South Asian (SAS) AF: 0.764 AC: 65916 AN: 86256

European-Finnish (FIN) AF: 0.780 AC: 41678 AN: 53400

Middle Eastern (MID) AF: 0.738 AC: 4251 AN: 5764

European-Non Finnish (NFE) AF: 0.692 AC: 769188 AN: 1111742

Other (OTH) AF: 0.697 AC: 42077 AN: 60384

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

African (AFR) AF: 0.629 AC: 26082 AN: 41458

American (AMR) AF: 0.707 AC: 10817 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2471 AN: 3470

East Asian (EAS) AF: 0.865 AC: 4459 AN: 5156

South Asian (SAS) AF: 0.773 AC: 3720 AN: 4814

European-Finnish (FIN) AF: 0.776 AC: 8209 AN: 10574

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47919 AN: 67956

Other (OTH) AF: 0.682 AC: 1438 AN: 2108

Alfa AF: 0.698 Hom.: 126511

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 25, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Macular degeneration, early-onset Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.6
DANN	Benign	0.80
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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