5-128311337-T-G

Position:

• chr5-128311337-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001999.4(FBN2):​c.5037A>C​(p.Gln1679His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.473

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 Uncertain_significance. Variant got 1 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=0.1984095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.5037A>C	p.Gln1679His	missense_variant	39/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4884A>C	p.Gln1628His	missense_variant	38/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.5037A>C	p.Gln1679His	missense_variant	39/65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.1821A>C		non_coding_transcript_exon_variant	14/38
FBN2	ENST00000703785.1	n.1740A>C		non_coding_transcript_exon_variant	13/27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 21, 2016

The p.Q1679H variant (also known as c.5037A>C), located in coding exon 39 of the FBN2 gene, results from an A to C substitution at nucleotide position 5037. The glutamine at codon 1679 is replaced by histidine, an amino acid with highly similar properties, and is located in the cb EGF-like #24 domain. This amino acid position is not well conserved in available vertebrate species, and histidine 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

Jul 12, 2022

ClinVar contains an entry for this variant (Variation ID: 519832). 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. This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1679 of the FBN2 protein (p.Gln1679His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.80	N;.;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.10	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.21
MutPred		0.60		Gain of catalytic residue at G1680 (P = 0.182);.;Gain of catalytic residue at G1680 (P = 0.182);
MVP		0.34
MPC		0.23
ClinPred		0.26	T
GERP RS		-5.1
Varity_R		0.062
gMVP		0.65

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: rs1554120349; hg19: chr5-127647029;