rs1554066013

Positions:

• chr5-128393260-T-A
• chr5-128393260-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001999.4(FBN2):​c.1340A>T​(p.Asn447Ile) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N447S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29160744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.1340A>T	p.Asn447Ile	missense_variant	10/65	ENST00000262464.9
FBN2	XM_017009228.3	c.1187A>T	p.Asn396Ile	missense_variant	9/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.1340A>T	p.Asn447Ile	missense_variant	10/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.1241A>T	p.Asn414Ile	missense_variant	9/33	2
FBN2	ENST00000703787.1	n.1047A>T		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.23	T;.;T;T
Eigen	Benign	0.025
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;.;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	0.60	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.40	T;.;T;T
Sift4G	Benign	0.24	.;.;.;T
Polyphen		0.97	D;.;D;D
Vest4		0.43
MutPred		0.40		Loss of phosphorylation at Y451 (P = 0.1165);.;Loss of phosphorylation at Y451 (P = 0.1165);.;
MVP		0.61
MPC		0.31
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.073
gMVP		0.51

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: rs1554066013; hg19: chr5-127728953; COSMIC: COSV52489689;