rs869025429

chr5-128273909-T-Cchr5-128273909-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001999.4(FBN2):c.7771A>G(p.Thr2591Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T2591P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.7771A>G	p.Thr2591Ala	missense_variant	61/65	ENST00000262464.9
FBN2	XM_017009228.3	c.7618A>G	p.Thr2540Ala	missense_variant	60/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.7771A>G	p.Thr2591Ala	missense_variant	61/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.4555A>G		non_coding_transcript_exon_variant	36/38

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 18, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;.
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D;.;D
REVEL	Uncertain	0.60
Sift	Benign	0.051	T;.;T
Polyphen		0.15	B;.;B
Vest4		0.53
MutPred		0.62		Loss of phosphorylation at T2591 (P = 0.1259);.;Loss of phosphorylation at T2591 (P = 0.1259);
MVP		0.84
MPC		0.27
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.17
gMVP		0.53

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: rs869025429; hg19: chr5-127609601;