chr5-128330633-G-T

Position:

• chr5-128330633-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001999.4(FBN2):​c.4285C>A​(p.Pro1429Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.65

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 5 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.
• PP5: Variant 5-128330633-G-T is Pathogenic according to our data. Variant chr5-128330633-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4285C>A	p.Pro1429Thr	missense_variant	33/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4132C>A	p.Pro1378Thr	missense_variant	32/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4285C>A	p.Pro1429Thr	missense_variant	33/65	1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2016

In summary, this variant is a novel missense change that was shown to arise de-novo in an affected individual and has an unknown effect on protein function. For these reasons it has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces proline with threonine at codon 1429 of the FBN2 protein (p.Pro1429Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. Family studies indicate this missense variant likely was not inherited from either parent (i.e. occurred de novo) in an individual with disease (Invitae database). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Benign	0.87
DEOGEN2	Uncertain	0.65	D;.;D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.11	T;.;T;T;T
Sift4G	Benign	0.57	.;.;.;T;T
Polyphen		0.27	B;.;B;.;D
Vest4		0.61
MutPred		0.51		Gain of catalytic residue at P1429 (P = 0.0071);.;Gain of catalytic residue at P1429 (P = 0.0071);.;.;
MVP		0.70
MPC		0.88
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.24
gMVP		0.81

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: rs1060503511; hg19: chr5-127666325;