rs1554119321

Variant names:

• chr5-128300928-C-T
• rs1554119321
• NM_001999.4:c.6055G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

The NM_001999.4(FBN2):​c.6055G>A​(p.Glu2019Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,166 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2019E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.16

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• BP6: Variant 5-128300928-C-T is Benign according to our data. Variant chr5-128300928-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458775.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6055G>A	p.Glu2019Lys	missense_variant	Exon 48 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.5902G>A	p.Glu1968Lys	missense_variant	Exon 47 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6055G>A	p.Glu2019Lys	missense_variant	Exon 48 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2839G>A		non_coding_transcript_exon_variant	Exon 23 of 38
FBN2	ENST00000703785.1	n.2758G>A		non_coding_transcript_exon_variant	Exon 22 of 27

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726948

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1 Benign:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant-negative is a suggested mechanism for congenital contractural arachnodactyly (MIM#121050) (PMID: 31316167). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Both inter and intra-famiial variability has been reported (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like repeat (uniprot, NCBI, DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Glu2019Gly) has been classified as a variant of uncertain significance by a diagnostic laboratory in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in an individual with FBN2-related disorder (PMID: 29907982). In addition, it has been classified as a variant of uncertain significance by a diagnostic laboratory in ClinVar. (I) 0904 - Non-segregation of this variant with the phenotype under investigation has been clearly demonstrated. The variant has previously been reported to be inherited from an individual's unaffected mother (PMID: 29907982). (SB) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2019 of the FBN2 protein (p.Glu2019Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of congenital contractural arachnodactyly and/or thoracic aortic aneurysm and/or dissection (PMID: 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 458775). 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 expected to disrupt FBN2 protein function with a positive predictive value of 80%. This variant disrupts the p.Glu2019 amino acid residue in FBN2. Other variant(s) that disrupt this residue have been observed in individuals with FBN2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;.;D
Polyphen		0.54	P;.;P
Vest4		0.90
MutPred		0.93		Gain of methylation at E2019 (P = 0.0038);.;Gain of methylation at E2019 (P = 0.0038);
MVP		0.94
MPC		0.78
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.64
gMVP		0.87

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: rs1554119321; hg19: chr5-127636620;