NM_001999.4:c.6253C>A

Variant names:

• chr5-128291568-G-T
• rs34845843
• NM_001999.4:c.6253C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_001999.4(FBN2):​c.6253C>A​(p.Pro2085Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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: 0.0000034 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.25

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6253C>A	p.Pro2085Thr	missense_variant	Exon 49 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6100C>A	p.Pro2034Thr	missense_variant	Exon 48 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6253C>A	p.Pro2085Thr	missense_variant	Exon 49 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3037C>A		non_coding_transcript_exon_variant	Exon 24 of 38
FBN2	ENST00000703785.1	n.2956C>A		non_coding_transcript_exon_variant	Exon 23 of 27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBN2 c.6253C>A; p.Pro2085Thr variant (rs34845843, ClinVar variation ID: 1677543) is reported in the literature in one individual affected with adolescent idiopathic scoliosis (Buchan 2014). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.745). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Buchan JG et al. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet. 2014 Oct 1;23(19):5271-82. PMID: 24833718. -

Oct 04, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Dec 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P2085T variant (also known as c.6253C>A), located in coding exon 49 of the FBN2 gene, results from a C to A substitution at nucleotide position 6253. The proline at codon 2085 is replaced by threonine, an amino acid with highly similar properties. This variant has been detected in an individual with severe scoliosis (Buchan JG et al. Hum Mol Genet, 2014 Oct;23:5271-82). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D;.;D
Eigen	Benign	-0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T;.;.
M_CAP	Pathogenic	0.63	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.80	N;.;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Pathogenic	0.74
Sift	Benign	0.26	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.43
MutPred		0.55		Loss of catalytic residue at P2084 (P = 0.0415);.;Loss of catalytic residue at P2084 (P = 0.0415);
MVP		0.41
MPC		0.44
ClinPred		0.33	T
GERP RS		4.4
Varity_R		0.20
gMVP		0.33

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: rs34845843; hg19: chr5-127627260;