5-128364663-C-T

Variant names:

• chr5-128364663-C-T
• rs886038969
• NM_001999.4:c.2365G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001999.4(FBN2):​c.2365G>A​(p.Gly789Ser) variant causes a missense change involving the alteration of a non-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: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.2365G>A	p.Gly789Ser	missense_variant	Exon 18 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.2212G>A	p.Gly738Ser	missense_variant	Exon 17 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2365G>A	p.Gly789Ser	missense_variant	Exon 18 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.2266G>A	p.Gly756Ser	missense_variant	Exon 17 of 33	2		ENSP00000425596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Mar 02, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G789S variant (also known as c.2365G>A), located in coding exon 18 of the FBN2 gene, results from a G to A substitution at nucleotide position 2365. The glycine at codon 789 is replaced by serine, an amino acid with some similar properties, and is located in the cb EGF-like #08 domain. 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. In the ESP, this variant was not observed in 6,503 samples (13,006 alleles) with coverage at this position. This amino acid position is well 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;.;.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;.;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D;.;D;D
Sift4G	Uncertain	0.0070	.;.;.;D
Polyphen		0.94	P;.;P;D
Vest4		0.52
MutPred		0.96		Gain of disorder (P = 0.0719);.;Gain of disorder (P = 0.0719);.;
MVP		0.89
MPC		0.34
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.70
gMVP		0.74

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: rs886038969; hg19: chr5-127700356;