rs957177447

chr5-128361770-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_001999.4(FBN2):c.2507C>T(p.Thr836Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T836S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.02

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 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.2507C>T	p.Thr836Met	missense_variant	19/65	ENST00000262464.9
FBN2	XM_017009228.3	c.2354C>T	p.Thr785Met	missense_variant	18/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.2507C>T	p.Thr836Met	missense_variant	19/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.2408C>T	p.Thr803Met	missense_variant	18/33	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251454 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with Usher syndrome who also harbored a second FBN2 variant and a MYH14 variant (Bahena et al., 2022); Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); This variant is associated with the following publications: (PMID: 34148116, 19006240, 18767143) -

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2023

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. ClinVar contains an entry for this variant (Variation ID: 561298). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 836 of the FBN2 protein (p.Thr836Met). -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T;.;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D;.;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.024	D;.;D;D
Polyphen		0.91	P;.;P;D
Vest4		0.53
MutPred		0.53		Loss of glycosylation at T836 (P = 0.0115);.;Loss of glycosylation at T836 (P = 0.0115);.;
MVP		0.47
MPC		0.80
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs957177447; hg19: chr5-127697463; COSMIC: COSV52518254; COSMIC: COSV52518254;