rs863223612

Positions:

• chr5-128288476-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001999.4(FBN2):​c.6719A>G​(p.Asn2240Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000082 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.16

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19235808).
• BP6: Variant 5-128288476-T-C is Benign according to our data. Variant chr5-128288476-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213421.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6719A>G	p.Asn2240Ser	missense_variant	53/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6566A>G	p.Asn2189Ser	missense_variant	52/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6719A>G	p.Asn2240Ser	missense_variant	53/65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3503A>G		non_coding_transcript_exon_variant	28/38
FBN2	ENST00000703785.1	n.3422A>G		non_coding_transcript_exon_variant	27/27

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135808

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727182

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2019	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009).; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 213421; Landrum et al., 2016) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 26, 2021	- -

Congenital contractural arachnodactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.17	N;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.36	N;.;N
REVEL	Benign	0.21
Sift	Benign	0.57	T;.;T
Polyphen		0.033	B;.;B
Vest4		0.28
MutPred		0.45		Gain of glycosylation at N2240 (P = 0.0776);.;Gain of glycosylation at N2240 (P = 0.0776);
MVP		0.45
MPC		0.19
ClinPred		0.44	T
GERP RS		4.7
Varity_R		0.033
gMVP		0.59

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: rs863223612; hg19: chr5-127624168;