5-128278799-A-T

Variant names:

• chr5-128278799-A-T
• rs28763926
• NM_001999.4:c.7181T>A

Variant summary

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

The NM_001999.4(FBN2):​c.7181T>A​(p.Ile2394Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I2394V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7181T>A	p.Ile2394Lys	missense_variant	Exon 57 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7028T>A	p.Ile2343Lys	missense_variant	Exon 56 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7181T>A	p.Ile2394Lys	missense_variant	Exon 57 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3965T>A		non_coding_transcript_exon_variant	Exon 32 of 38

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.046
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		7.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.039	D;.;D
Polyphen		0.14	B;.;B
Vest4		0.44
MutPred		0.63		Gain of disorder (P = 0.0038);.;Gain of disorder (P = 0.0038);
MVP		0.35
MPC		0.47
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.75
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28763926; hg19: chr5-127614491;