Variant 3-13571008-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001004019.2(FBLN2):c.653C>T(p.Ala218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,445,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

FBLN2
NM_001004019.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

FBLN2 (HGNC:3601): (fibulin 2) This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FBLN2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FBLN2	NM_001004019.2 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/18	ENST00000404922.8
FBLN2	NM_001165035.2 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/18
FBLN2	NM_001998.3 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBLN2	ENST00000404922.8 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/18	5	NM_001004019.2	P1	P98095-2
FBLN2	ENST00000295760.11 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/17	1			P98095-1
FBLN2	ENST00000492059.5 linkuse as main transcript	c.653C>T	p.Ala218Val	missense_variant	2/18	2		P1	P98095-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000184

AC:

AN:

217346

Hom.:

AF XY:

0.0000254

AC XY:

AN XY:

118030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000311

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1445528

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

717714

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000398

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.653C>T (p.A218V) alteration is located in exon 2 (coding exon 1) of the FBLN2 gene. This alteration results from a C to T substitution at nucleotide position 653, causing the alanine (A) at amino acid position 218 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.45

.;T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.0

N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.20

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.058

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.31

MVP

0.73

MPC

0.39

ClinPred

0.13

GERP RS

0.93

Varity_R

0.036

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over