rs143515269

Positions:

• chr5-128393267-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001999.4(FBN2):​c.1333A>G​(p.Ser445Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.155

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 Benign. Variant got -8 ACMG points.

• 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=0.061564177).
• BP6: Variant 5-128393267-T-C is Benign according to our data. Variant chr5-128393267-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.1333A>G	p.Ser445Gly	missense_variant	10/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1180A>G	p.Ser394Gly	missense_variant	9/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.1333A>G	p.Ser445Gly	missense_variant	10/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000508989.5	c.1234A>G	p.Ser412Gly	missense_variant	9/33	2		ENSP00000425596
FBN2	ENST00000703787.1	n.1040A>G		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 250950 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009).; This variant is associated with the following publications: (PMID: 26582918, 18767143, 27535533) -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.16	T;.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.71	T;.;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.0	N;.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.96	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.41	T;.;T;T
Sift4G	Benign	0.46	.;.;.;T
Polyphen		0.0	B;.;B;B
Vest4		0.17
MVP		0.40
MPC		0.21
ClinPred		0.025	T
GERP RS		-2.3
Varity_R		0.023
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143515269; hg19: chr5-127728960;