rs34845843

Positions:

• chr5-128291568-G-A
• chr5-128291568-G-C
• chr5-128291568-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000262464.9(FBN2):​c.6253C>T​(p.Pro2085Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2085A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 ENST00000262464.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6253C>T	p.Pro2085Ser	missense_variant	49/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6100C>T	p.Pro2034Ser	missense_variant	48/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6253C>T	p.Pro2085Ser	missense_variant	49/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000703783.1	n.3037C>T		non_coding_transcript_exon_variant	24/38
FBN2	ENST00000703785.1	n.2956C>T		non_coding_transcript_exon_variant	23/27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;D
Eigen	Benign	-0.076
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.71	T;.;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.25	N;.;N
MutationTaster	Benign	0.51	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;.;D
REVEL	Uncertain	0.48
Sift	Benign	0.35	T;.;T
Polyphen		0.090	B;.;B
Vest4		0.39
MutPred		0.54		Loss of catalytic residue at P2084 (P = 0.0415);.;Loss of catalytic residue at P2084 (P = 0.0415);
MVP		0.58
MPC		0.79
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs34845843; hg19: chr5-127627260; COSMIC: COSV99325473;