3-13570555-G-A

Variant names:

• chr3-13570555-G-A
• rs374266208
• NM_001004019.2:c.200G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001004019.2(FBLN2):​c.200G>A​(p.Gly67Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000377 in 1,590,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: FBLN2 NM_001004019.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.320141).
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004019.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	NM_001004019.2	MANE Select	c.200G>A	p.Gly67Asp	missense	Exon 2 of 18	NP_001004019.1	P98095-2
	FBLN2	NM_001165035.2		c.200G>A	p.Gly67Asp	missense	Exon 2 of 18	NP_001158507.1	P98095-2
	FBLN2	NM_001998.3		c.200G>A	p.Gly67Asp	missense	Exon 2 of 17	NP_001989.2	P98095-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	ENST00000404922.8	TSL:5 MANE Select	c.200G>A	p.Gly67Asp	missense	Exon 2 of 18	ENSP00000384169.3	P98095-2
	FBLN2	ENST00000295760.11	TSL:1	c.200G>A	p.Gly67Asp	missense	Exon 2 of 17	ENSP00000295760.7	P98095-1
	FBLN2	ENST00000492059.5	TSL:2	c.200G>A	p.Gly67Asp	missense	Exon 2 of 18	ENSP00000420042.1	P98095-2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000643 AC: 13 AN: 202260 AF XY: 0.0000543

Gnomad AFR exome AF: 0.0000897

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000114

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.0000383 AC: 55 AN: 1437760 Hom.: 0 Cov.: 34 AF XY: 0.0000351 AC XY: 25 AN XY: 712902

African (AFR) AF: 0.00 AC: 0 AN: 33122

American (AMR) AF: 0.0000241 AC: 1 AN: 41484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25600

East Asian (EAS) AF: 0.00 AC: 0 AN: 38598

South Asian (SAS) AF: 0.000389 AC: 32 AN: 82318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1101758

Other (OTH) AF: 0.0000672 AC: 4 AN: 59494

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74482

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000357 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000501 AC: 6

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.48
MPC		0.65
ClinPred		0.41	T
GERP RS		5.0
Varity_R		0.81
gMVP		0.78
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs374266208; hg19: chr3-13612055;