rs73348287

Variant names:

• chr5-128537421-G-C
• rs73348287
• NM_001999.4:c.183C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.183C>G​(p.Pro61Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,609,328 control chromosomes in the GnomAD database, including 6,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (925 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5460 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.54
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-128537421-G-C is Benign according to our data. Variant chr5-128537421-G-C is described in ClinVar as Benign. ClinVar VariationId is 129036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.183C>G	p.Pro61Pro	synonymous_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.183C>G	p.Pro61Pro	synonymous_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.183C>G	p.Pro61Pro	synonymous_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15692 AN: 152092 Hom.: 921 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.00543

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0850

Gnomad OTH AF: 0.0872

GnomAD2 exomes AF: 0.0789 AC: 18852 AN: 239022 AF XY: 0.0783

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0529

Gnomad ASJ exome AF: 0.0737

Gnomad EAS exome AF: 0.00178

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0833 AC: 121307 AN: 1457122 Hom.: 5460 Cov.: 33 AF XY: 0.0831 AC XY: 60254 AN XY: 724674

African (AFR) AF: 0.167 AC: 5595 AN: 33458

American (AMR) AF: 0.0545 AC: 2425 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.0731 AC: 1902 AN: 26014

East Asian (EAS) AF: 0.0110 AC: 438 AN: 39658

South Asian (SAS) AF: 0.0850 AC: 7274 AN: 85528

European-Finnish (FIN) AF: 0.0785 AC: 3993 AN: 50890

Middle Eastern (MID) AF: 0.0765 AC: 441 AN: 5762

European-Non Finnish (NFE) AF: 0.0849 AC: 94362 AN: 1111082

Other (OTH) AF: 0.0810 AC: 4877 AN: 60218

GnomAD4 genome AF: 0.103 AC: 15722 AN: 152206 Hom.: 925 Cov.: 33 AF XY: 0.101 AC XY: 7518 AN XY: 74418

African (AFR) AF: 0.170 AC: 7058 AN: 41542

American (AMR) AF: 0.0648 AC: 991 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 281 AN: 3472

East Asian (EAS) AF: 0.00545 AC: 28 AN: 5142

South Asian (SAS) AF: 0.0773 AC: 373 AN: 4826

European-Finnish (FIN) AF: 0.0869 AC: 921 AN: 10604

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0850 AC: 5780 AN: 68006

Other (OTH) AF: 0.0858 AC: 181 AN: 2110

Alfa AF: 0.0877 Hom.: 211

Bravo AF: 0.103

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 16, 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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro61Pro in exon 1 of FBN2: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 17.0% (745/4394) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs73348287). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:4

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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. -

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. -

not provided Benign:1

Nov 22, 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	-0.84
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-1.5
PromoterAI		0.016	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73348287; hg19: chr5-127873114;