rs1554066013

chr5-128393260-T-Achr5-128393260-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 where missense usually causes diseases, FBN2
• 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
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;