rs1554120349

Variant names:

• chr5-128311337-T-G
• rs1554120349
• NM_001999.4:c.5037A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001999.4(FBN2):​c.5037A>C​(p.Gln1679His) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.473
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1984095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.5037A>C	p.Gln1679His	missense	Exon 39 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.5037A>C	p.Gln1679His	missense	Exon 39 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.4938A>C	p.Gln1646His	missense	Exon 38 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.4884A>C	p.Gln1628His	missense	Exon 38 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital contractural arachnodactyly (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.80	N
PhyloP100		-0.47
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.30
Sift	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.60		Gain of catalytic residue at G1680 (P = 0.182)
MVP		0.34
MPC		0.23
ClinPred		0.26	T
GERP RS		-5.1
Varity_R		0.062
gMVP		0.65
Mutation Taster		=76/24	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: rs1554120349; hg19: chr5-127647029;