rs765437414

Variant names:

• chr5-128344438-T-C
• NM_001999.4:c.3290A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128344438-T-C
• chr5-128344438-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001999.4(FBN2):​c.3290A>G​(p.Lys1097Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.02

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.30041426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3290A>G	p.Lys1097Arg	missense_variant	Exon 25 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3137A>G	p.Lys1046Arg	missense_variant	Exon 24 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3290A>G	p.Lys1097Arg	missense_variant	Exon 25 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.3191A>G	p.Lys1064Arg	missense_variant	Exon 24 of 33	2		ENSP00000425596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

May 17, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1097R variant (also known as c.3290A>G), located in coding exon 25 of the FBN2 gene, results from an A to G substitution at nucleotide position 3290. The lysine at codon 1097 is replaced by arginine, an amino acid with highly similar properties, and is located in a cbEGF-like domain. This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly Uncertain:1

Feb 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 1729843). This missense change has been observed in individual(s) with FBN2-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1097 of the FBN2 protein (p.Lys1097Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Benign	0.23	T;.;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.030	N;.;N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.54	N;.;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.43	T;.;T;T
Sift4G	Benign	0.85	.;.;.;T
Polyphen		0.0030	B;.;B;B
Vest4		0.21
MutPred		0.62		Loss of methylation at K1097 (P = 0.0022);.;Loss of methylation at K1097 (P = 0.0022);.;
MVP		0.87
MPC		0.20
ClinPred		0.42	T
GERP RS		4.3
Varity_R		0.078
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127680130;