chr5-128537536-G-T

Variant names:

• chr5-128537536-G-T
• rs199560824
• NM_001999.4:c.68C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001999.4(FBN2):​c.68C>A​(p.Ala23Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19667909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.68C>A	p.Ala23Glu	missense_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.68C>A	p.Ala23Glu	missense_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.68C>A	p.Ala23Glu	missense_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438600 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 714138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000471

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Feb 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glutamic acid at codon 23 of the FBN2 protein (p.Ala23Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. 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. This variant has not been reported in the literature in individuals with FBN2-related disease. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;.;T;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T;.;.;T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.55	N;.;N;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.83	N;.;N;N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D
Polyphen		0.0010	B;.;B;B;B
Vest4		0.43
MutPred		0.38		Loss of MoRF binding (P = 0.066);Loss of MoRF binding (P = 0.066);Loss of MoRF binding (P = 0.066);Loss of MoRF binding (P = 0.066);Loss of MoRF binding (P = 0.066);
MVP		0.16
MPC		0.27
ClinPred		0.51	D
GERP RS		0.77
Varity_R		0.27
gMVP		0.77

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: rs199560824; hg19: chr5-127873229;