rs1461140915

Positions:

• chr5-128280218-G-A
• chr5-128280218-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001999.4(FBN2):​c.7112C>T​(p.Ser2371Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11118069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7112C>T	p.Ser2371Leu	missense_variant	56/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6959C>T	p.Ser2320Leu	missense_variant	55/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7112C>T	p.Ser2371Leu	missense_variant	56/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000703783.1	n.3896C>T		non_coding_transcript_exon_variant	31/38

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250940 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.60	N;.;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.83	T;.;T
Polyphen		0.0070	B;.;B
Vest4		0.22
MutPred		0.53		Loss of disorder (P = 0.0292);.;Loss of disorder (P = 0.0292);
MVP		0.32
MPC		0.21
ClinPred		0.32	T
GERP RS		4.1
Varity_R		0.096
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1461140915; hg19: chr5-127615910; COSMIC: COSV52509999;