chr5-128393260-T-A

Variant names:

• chr5-128393260-T-A
• rs1554066013
• NM_001999.4:c.1340A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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. 13/22 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
• Publications: 0 publications found

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]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29160744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.1340A>T	p.Asn447Ile	missense_variant	Exon 10 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1187A>T	p.Asn396Ile	missense_variant	Exon 9 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.1340A>T	p.Asn447Ile	missense_variant	Exon 10 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.1241A>T	p.Asn414Ile	missense_variant	Exon 9 of 33	2		ENSP00000425596.1
FBN2	ENST00000703787.1	n.1047A>T		non_coding_transcript_exon_variant	Exon 9 of 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;.
PhyloP100		2.4
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
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

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