rs2291628

chr5-128273941-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):c.7739C>T(p.Ser2580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 1,613,668 control chromosomes in the GnomAD database, including 4,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2580S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.071 (436 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4394 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.193

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.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017172396).
• BP6: Variant 5-128273941-G-A is Benign according to our data. Variant chr5-128273941-G-A is described in ClinVar as [Benign]. Clinvar id is 129051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128273941-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.7739C>T	p.Ser2580Leu	missense_variant	61/65	ENST00000262464.9
FBN2	XM_017009228.3	c.7586C>T	p.Ser2529Leu	missense_variant	60/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.7739C>T	p.Ser2580Leu	missense_variant	61/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.4523C>T		non_coding_transcript_exon_variant	36/38

Frequencies

GnomAD3 genomes AF: 0.0707 AC: 10753 AN: 152072 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.0891

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.0681

GnomAD3 exomes AF: 0.0741 AC: 18579 AN: 250880 Hom.: 752 AF XY: 0.0736 AC XY: 9979 AN XY: 135562

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.0839

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0603

Gnomad SAS exome AF: 0.0809

Gnomad FIN exome AF: 0.0440

Gnomad NFE exome AF: 0.0735

Gnomad OTH exome AF: 0.0735

GnomAD4 exome AF: 0.0750 AC: 109644 AN: 1461478 Hom.: 4394 Cov.: 32 AF XY: 0.0753 AC XY: 54738 AN XY: 727060

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0616

Gnomad4 SAS exome AF: 0.0811

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.0813

GnomAD4 genome AF: 0.0706 AC: 10751 AN: 152190 Hom.: 436 Cov.: 32 AF XY: 0.0683 AC XY: 5083 AN XY: 74402

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.0693

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0629

Gnomad4 SAS AF: 0.0882

Gnomad4 FIN AF: 0.0347

Gnomad4 NFE AF: 0.0718

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0728 Hom.: 974

Bravo AF: 0.0733

TwinsUK AF: 0.0761 AC: 282

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0813 AC: 358

ESP6500EA AF: 0.0764 AC: 657

ExAC AF: 0.0743 AC: 9017

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0733

EpiControl AF: 0.0751

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ser2580Leu in exon 61 of FBN2: This variant is not expected to have clinical sig nificance because it has been identified in 8.1% (358/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2291628). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Congenital contractural arachnodactyly Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	Feb 04, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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.7739C>T (p.Ser2580Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. The variant of interest has been observed in a large, broad control population, ExAC, in 9006/121038 control chromosomes (359 homozygotes) at a frequency of 0.0744064, which is approximately 59525 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 classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	T;.;.
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;.;D
REVEL	Benign	0.23
Sift	Uncertain	0.029	D;.;D
Polyphen		0.0010	B;.;B
Vest4		0.19
MPC		0.22
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.14
gMVP		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

Other links and lift over

dbSNP: rs2291628; hg19: chr5-127609633; COSMIC: COSV52516875;