5-128339011-C-T

Position:

• chr5-128339011-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_001999.4(FBN2):​c.3394G>A​(p.Val1132Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000288 in 1,613,794 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. V1132V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 5.06

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.

• PP2: Missense variant where missense usually causes diseases, FBN2
• BP6: Variant 5-128339011-C-T is Benign according to our data. Variant chr5-128339011-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213228.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=3}. Variant chr5-128339011-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000197 (30/152170) while in subpopulation NFE AF= 0.000338 (23/68032). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3394G>A	p.Val1132Ile	missense_variant	26/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3241G>A	p.Val1081Ile	missense_variant	25/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3394G>A	p.Val1132Ile	missense_variant	26/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251394 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135872

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000298 AC: 435 AN: 1461624 Hom.: 0 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74342

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The FBN2 c.3394G>A; p.Val1132Ile variant (rs138834515) is reported in the literature in a family affected with adolescent idiopathic scoliosis, although it was not demonstrated to be causative (Jiang 2020). This variant is found in the general population with an overall allele frequency of 0.02% (48/282800 alleles) in the Genome Aggregation Database. The valine at codon 1132 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.431). However, due to limited information, the clinical significance of the p.Val1132Ile variant is uncertain at this time. References: Jiang et al. Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis. J Med Genet. 2020 Jun;57(6):405-413. PMID: 32381728. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24205039, 32381728) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	- -

Congenital contractural arachnodactyly Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The p.V1132I variant (also known as c.3394G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3394. The valine at codon 1132 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FBN2 NM_001999.3 exon 26 p.Val1132Ile (c.3394G>A): This variant has not been reported in the literature and is present in 0.03% (7/19946) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-127674703-C-T). This variant is present in ClinVar (Variation ID:213228). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;T
Eigen	Benign	0.093
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;.;.;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.10	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.82	N;.;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.041	D;.;D;T
Polyphen		0.054	B;.;B;P
Vest4		0.41
MVP		0.70
MPC		0.31
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs138834515; hg19: chr5-127674703;