rs1060503509

Positions:

• chr5-128537452-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001999.4(FBN2):​c.152C>G​(p.Thr51Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,454,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0700

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.049115807).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.152C>G	p.Thr51Arg	missense_variant	1/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.152C>G	p.Thr51Arg	missense_variant	1/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.152C>G	p.Thr51Arg	missense_variant	1/65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454952 Hom.: 0 Cov.: 33 AF XY: 0.00000553 AC XY: 4 AN XY: 723404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000811

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

FBN2: PM2 -

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 411833). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 51 of the FBN2 protein (p.Thr51Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.2
DANN	Benign	0.82
DEOGEN2	Benign	0.15	T;.;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.81	T;.;.;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.049	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.63	N;.;N;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.18	N;.;N;N;N
REVEL	Benign	0.074
Sift	Benign	0.19	T;.;T;T;T
Sift4G	Benign	0.54	.;.;.;T;T
Polyphen		0.037	B;.;B;B;B
Vest4		0.23
MutPred		0.37		Loss of phosphorylation at T51 (P = 0.0137);Loss of phosphorylation at T51 (P = 0.0137);Loss of phosphorylation at T51 (P = 0.0137);Loss of phosphorylation at T51 (P = 0.0137);Loss of phosphorylation at T51 (P = 0.0137);
MVP		0.30
MPC		0.27
ClinPred		0.15	T
GERP RS		0.52
Varity_R		0.064
gMVP		0.61

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: rs1060503509; hg19: chr5-127873145;