5-128318239-C-T

Variant names:

• chr5-128318239-C-T
• rs1554121038
• NM_001999.4:c.4627G>A

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.4627G>A​(p.Val1543Ile) 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. 14/22 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, single submitter U:1
• Conservation: PhyloP100: 1.42
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25609082).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.4627G>A	p.Val1543Ile	missense	Exon 36 of 65	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.4627G>A	p.Val1543Ile	missense	Exon 36 of 65	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.4528G>A	p.Val1510Ile	missense	Exon 35 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.4474G>A	p.Val1492Ile	missense	Exon 35 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital contractural arachnodactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.28
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.56	N
PhyloP100		1.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.36	N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.21
MutPred		0.52		Loss of catalytic residue at V1543 (P = 0.0866)
MVP		0.30
MPC		0.21
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.076
gMVP		0.70
Mutation Taster		=89/11	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: rs1554121038; hg19: chr5-127653931;