rs1060503506

Positions:

• chr5-128530606-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001999.4(FBN2):​c.425G>C​(p.Gly142Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.93

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.39408803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.425G>C	p.Gly142Ala	missense_variant	3/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.425G>C	p.Gly142Ala	missense_variant	3/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.425G>C	p.Gly142Ala	missense_variant	3/65	1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457524 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725414

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2020

The p.G142A variant (also known as c.425G>C), located in coding exon 3 of the FBN2 gene, results from a G to C substitution at nucleotide position 425. The glycine at codon 142 is replaced by alanine, an amino acid with similar properties, and is located in the EGF-like #02 domain. This amino acid position is well conserved in available vertebrate species; however, alanine is the reference amino acid in other 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 142 of the FBN2 protein (p.Gly142Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant has not been reported in the literature in individuals affected with FBN2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;.;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;.;.;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.094	T;.;T;D
Sift4G	Benign	0.28	.;.;.;T
Polyphen		0.94	P;.;P;D
Vest4		0.42
MutPred		0.26		Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);Gain of catalytic residue at G142 (P = 0.1172);
MVP		0.86
MPC		0.25
ClinPred		0.91	D
GERP RS		3.7
Varity_R		0.17
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1060503506; hg19: chr5-127866299;