rs886038935

Variant names:

• chr5-128332950-C-A
• rs886038935
• NM_001999.4:c.4184G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128332950-C-A
• chr5-128332950-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001999.4(FBN2):​c.4184G>T​(p.Cys1395Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain EGF-like 22; calcium-binding (size 40) in uniprot entity FBN2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001999.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4184G>T	p.Cys1395Phe	missense_variant	Exon 32 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4031G>T	p.Cys1344Phe	missense_variant	Exon 31 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4184G>T	p.Cys1395Phe	missense_variant	Exon 32 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Feb 21, 2014

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C1395F variant (also known as c.4184G>T), located in coding exon 32 of the FBN2 gene in the cb EGF-like #19 domain, results from a G to T substitution at nucleotide position 4184. The cysteine at codon 1395 is replaced by phenylalanine, an amino acid with highly dissimilar properties. In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and seven of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.2	H;.;H;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	D;.;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		1.0
MutPred		0.99		Loss of ubiquitination at K1392 (P = 0.1264);.;Loss of ubiquitination at K1392 (P = 0.1264);.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		1.0
gMVP		0.99

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: rs886038935; hg19: chr5-127668642;