chr3-13570471-C-T

Variant names:

• chr3-13570471-C-T
• rs369825172
• NM_001004019.2:c.116C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001004019.2(FBLN2):​c.116C>T​(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000951 in 1,577,432 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 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: FBLN2 NM_001004019.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25938398).
• BS2: High AC in GnomAdExome4 at 14 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.116C>T	p.Pro39Leu	missense	Exon 2 of 18	NP_001004019.1	P98095-2
	FBLN2	NM_001165035.2		c.116C>T	p.Pro39Leu	missense	Exon 2 of 18	NP_001158507.1	P98095-2
	FBLN2	NM_001998.3		c.116C>T	p.Pro39Leu	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.116C>T	p.Pro39Leu	missense	Exon 2 of 18	ENSP00000384169.3	P98095-2
	FBLN2	ENST00000295760.11	TSL:1	c.116C>T	p.Pro39Leu	missense	Exon 2 of 17	ENSP00000295760.7	P98095-1
	FBLN2	ENST00000492059.5	TSL:2	c.116C>T	p.Pro39Leu	missense	Exon 2 of 18	ENSP00000420042.1	P98095-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000158 AC: 3 AN: 190346 AF XY: 0.00000961

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.00000982 AC: 14 AN: 1425108 Hom.: 0 Cov.: 33 AF XY: 0.00000709 AC XY: 5 AN XY: 704940

African (AFR) AF: 0.0000305 AC: 1 AN: 32788

American (AMR) AF: 0.00 AC: 0 AN: 40116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25438

East Asian (EAS) AF: 0.00 AC: 0 AN: 37802

South Asian (SAS) AF: 0.00 AC: 0 AN: 81444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48414

Middle Eastern (MID) AF: 0.000368 AC: 2 AN: 5440

European-Non Finnish (NFE) AF: 0.00000913 AC: 10 AN: 1094778

Other (OTH) AF: 0.0000170 AC: 1 AN: 58888

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000337 AC: 4

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	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.24
MVP		0.41
MPC		0.14
ClinPred		0.68	D
GERP RS		4.1
Varity_R		0.079
gMVP		0.65
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs369825172; hg19: chr3-13611971;