rs34845843

chr5-128291568-G-Achr5-128291568-G-Cchr5-128291568-G-T

Variant summary

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

The NM_001999.4(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 NM_001999.4 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 where missense usually causes diseases, FBN2

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.6253C>T	p.Pro2085Ser	missense_variant	49/65	1	NM_001999.4	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;