rs572453085

Variant names:

• chr5-128273953-C-A
• rs572453085
• NM_001999.4:c.7727G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001999.4(FBN2):​c.7727G>T​(p.Gly2576Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2665496).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7727G>T	p.Gly2576Val	missense_variant	Exon 61 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7574G>T	p.Gly2525Val	missense_variant	Exon 60 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7727G>T	p.Gly2576Val	missense_variant	Exon 61 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.4511G>T		non_coding_transcript_exon_variant	Exon 36 of 38
FBN2	ENST00000703784.1	n.-107G>T		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727140

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Jan 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with valine at codon 2576 of the FBN2 protein (p.Gly2576Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC 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. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN2-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;.;.
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	-0.86	N;.;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.98	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.29	T;.;T
Polyphen		0.021	B;.;B
Vest4		0.32
MutPred		0.49		Loss of disorder (P = 0.0255);.;Loss of disorder (P = 0.0255);
MVP		0.38
MPC		0.30
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.44

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: rs572453085; hg19: chr5-127609645; COSMIC: COSV99331671;