NM_001004019.2:c.3612C>T

Variant names:

• chr3-13637835-C-T
• rs1061376
• NM_001004019.2:c.3612C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001004019.2(FBLN2):​c.3612C>T​(p.Asp1204Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,034 control chromosomes in the GnomAD database, including 97,526 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.41 (14326 hom., cov: 33)
  • Exomes 𝑓: 0.33 (83200 hom.)
• Consequence: FBLN2 NM_001004019.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 15 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	NM_001004019.2	MANE Select	c.3612C>T	p.Asp1204Asp	synonymous	Exon 18 of 18	NP_001004019.1
	FBLN2	NM_001165035.2		c.3612C>T	p.Asp1204Asp	synonymous	Exon 18 of 18	NP_001158507.1
	FBLN2	NM_001998.3		c.3471C>T	p.Asp1157Asp	synonymous	Exon 17 of 17	NP_001989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	ENST00000404922.8	TSL:5 MANE Select	c.3612C>T	p.Asp1204Asp	synonymous	Exon 18 of 18	ENSP00000384169.3
	FBLN2	ENST00000295760.11	TSL:1	c.3471C>T	p.Asp1157Asp	synonymous	Exon 17 of 17	ENSP00000295760.7
	FBLN2	ENST00000492059.5	TSL:2	c.3612C>T	p.Asp1204Asp	synonymous	Exon 18 of 18	ENSP00000420042.1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62227 AN: 151978 Hom.: 14301 Cov.: 33

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.370 AC: 91892 AN: 248504 AF XY: 0.362

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.675

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.329 AC: 480009 AN: 1460938 Hom.: 83200 Cov.: 44 AF XY: 0.328 AC XY: 238582 AN XY: 726610

African (AFR) AF: 0.621 AC: 20785 AN: 33470

American (AMR) AF: 0.381 AC: 17037 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 8282 AN: 26128

East Asian (EAS) AF: 0.630 AC: 24988 AN: 39670

South Asian (SAS) AF: 0.350 AC: 30144 AN: 86220

European-Finnish (FIN) AF: 0.283 AC: 15084 AN: 53286

Middle Eastern (MID) AF: 0.391 AC: 2252 AN: 5758

European-Non Finnish (NFE) AF: 0.306 AC: 339536 AN: 1111362

Other (OTH) AF: 0.363 AC: 21901 AN: 60336

GnomAD4 genome AF: 0.410 AC: 62301 AN: 152096 Hom.: 14326 Cov.: 33 AF XY: 0.409 AC XY: 30418 AN XY: 74344

African (AFR) AF: 0.602 AC: 24981 AN: 41496

American (AMR) AF: 0.385 AC: 5887 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1123 AN: 3468

East Asian (EAS) AF: 0.661 AC: 3415 AN: 5166

South Asian (SAS) AF: 0.358 AC: 1725 AN: 4822

European-Finnish (FIN) AF: 0.272 AC: 2879 AN: 10578

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20920 AN: 67954

Other (OTH) AF: 0.402 AC: 850 AN: 2114

Alfa AF: 0.346 Hom.: 41589

Bravo AF: 0.430

Asia WGS AF: 0.514 AC: 1786 AN: 3478

EpiCase AF: 0.326

EpiControl AF: 0.330

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	6.2
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1061376; hg19: chr3-13679335; COSMIC: COSV55482241;