chr5-128537494-G-A

Variant names:

• chr5-128537494-G-A
• rs201255083
• NM_001999.4:c.110C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001999.4(FBN2):​c.110C>T​(p.Pro37Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,433,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P37Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.410
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16544583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711030

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.00 AC: 0 AN: 41192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 38348

South Asian (SAS) AF: 0.00 AC: 0 AN: 83062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100676

Other (OTH) AF: 0.00 AC: 0 AN: 59360

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 37 of the FBN2 protein (p.Pro37Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBN2 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.88	D;.;.;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N;.;N;.;.
PhyloP100		0.41
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;.;T;T;T
Sift4G	Benign	0.15	.;.;.;T;D
Polyphen		0.025	B;.;B;B;B
Vest4		0.20
MutPred		0.32		Loss of glycosylation at P37 (P = 0.0025);Loss of glycosylation at P37 (P = 0.0025);Loss of glycosylation at P37 (P = 0.0025);Loss of glycosylation at P37 (P = 0.0025);Loss of glycosylation at P37 (P = 0.0025);
MVP		0.48
MPC		0.24
ClinPred		0.21	T
GERP RS		2.9
PromoterAI		-0.020	Neutral
Varity_R		0.045
gMVP		0.43
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs201255083; hg19: chr5-127873187;