rs555068280

chr5-128536449-CAGT-Cchr5-128536449-CAGT-CAGTAGT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001999.4(FBN2):c.287_289del(p.Tyr96del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y96Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: FBN2 NM_001999.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 9.23

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001999.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-128536449-CAGT-C is Benign according to our data. Variant chr5-128536449-CAGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000224 (328/1461764) while in subpopulation AMR AF= 0.000917 (41/44716). AF 95% confidence interval is 0.000694. There are 0 homozygotes in gnomad4_exome. There are 144 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.287_289del	p.Tyr96del	inframe_deletion	2/65	ENST00000262464.9
FBN2	XM_017009228.3	c.287_289del	p.Tyr96del	inframe_deletion	2/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.287_289del	p.Tyr96del	inframe_deletion	2/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000212 AC: 53 AN: 250414 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000224 AC: 328 AN: 1461764 Hom.: 0 AF XY: 0.000198 AC XY: 144 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000215

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 2021	The c.287_289delACT variant (also known as p.Y96del) is located in coding exon 2 of the FBN2 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 287 to 289. This results in the deletion of a tyrosine residue at codon 96. This variant was reported once in an exome pulmonary nontuberculous mycobacterial infection cohort; however, clinical details were limited (Szymanski EP et al. Am J Respir Crit Care Med, 2015 Sep;192:618-28). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2013	There is insufficient or conflicting evidence for classification of this alteration. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2023

Has been reported in one patient with pulmonary nontuberculous mycobacteria (Szymanski et al., 2015); although members of this study cohort were evaluated for associated connective tissue features, no patient-specific clinical data or family member data were included for this variant; In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of a tyrosine residue at codon 96, in a non-repeat region; Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); This variant is associated with the following publications: (PMID: 26038974) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 06, 2023

Variant summary: FBN2 c.287_289delACT (p.Tyr96del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00021 in 250414 control chromosomes. The observed variant frequency is approximately 169.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.287_289delACT has been reported in the literature in a patient with pulmonary nontuberculous mycobacteria infection, without strong evidence for causality (Szymanksi_2015). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26038974). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: two classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

FBN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs555068280; hg19: chr5-127872142;