3-13629276-T-C

Variant names:

• chr3-13629276-T-C
• rs4684968
• NM_001004019.2:c.2826T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001004019.2(FBLN2):​c.2826T>C​(p.Phe942Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,610,110 control chromosomes in the GnomAD database, including 379,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39293 hom., cov: 36)
  • Exomes 𝑓: 0.68 (340242 hom.)
• Consequence: FBLN2 NM_001004019.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.338
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-13629276-T-C is Benign according to our data. Variant chr3-13629276-T-C is described in ClinVar as Benign. ClinVar VariationId is 1342035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN2	NM_001004019.2	c.2826T>C	p.Phe942Phe	synonymous_variant	Exon 13 of 18	ENST00000404922.8	NP_001004019.1
FBLN2	NM_001165035.2	c.2826T>C	p.Phe942Phe	synonymous_variant	Exon 13 of 18		NP_001158507.1
FBLN2	NM_001998.3	c.2685T>C	p.Phe895Phe	synonymous_variant	Exon 12 of 17		NP_001989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN2	ENST00000404922.8	c.2826T>C	p.Phe942Phe	synonymous_variant	Exon 13 of 18	5	NM_001004019.2	ENSP00000384169.3
FBLN2	ENST00000295760.11	c.2685T>C	p.Phe895Phe	synonymous_variant	Exon 12 of 17	1		ENSP00000295760.7
FBLN2	ENST00000492059.5	c.2826T>C	p.Phe942Phe	synonymous_variant	Exon 13 of 18	2		ENSP00000420042.1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108743 AN: 152092 Hom.: 39268 Cov.: 36

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.729 AC: 177123 AN: 242876 AF XY: 0.723

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.851

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.710

GnomAD4 exome AF: 0.679 AC: 990128 AN: 1457900 Hom.: 340242 Cov.: 69 AF XY: 0.680 AC XY: 492868 AN XY: 725042

African (AFR) AF: 0.758 AC: 25347 AN: 33422

American (AMR) AF: 0.844 AC: 37527 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 15511 AN: 26052

East Asian (EAS) AF: 0.989 AC: 39186 AN: 39618

South Asian (SAS) AF: 0.759 AC: 65059 AN: 85760

European-Finnish (FIN) AF: 0.719 AC: 37874 AN: 52706

Middle Eastern (MID) AF: 0.685 AC: 3512 AN: 5126

European-Non Finnish (NFE) AF: 0.653 AC: 724683 AN: 1110580

Other (OTH) AF: 0.688 AC: 41429 AN: 60196

GnomAD4 genome AF: 0.715 AC: 108819 AN: 152210 Hom.: 39293 Cov.: 36 AF XY: 0.721 AC XY: 53663 AN XY: 74422

African (AFR) AF: 0.755 AC: 31365 AN: 41560

American (AMR) AF: 0.775 AC: 11867 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3470

East Asian (EAS) AF: 0.984 AC: 5089 AN: 5172

South Asian (SAS) AF: 0.768 AC: 3713 AN: 4832

European-Finnish (FIN) AF: 0.724 AC: 7678 AN: 10602

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44717 AN: 67958

Other (OTH) AF: 0.705 AC: 1489 AN: 2112

Alfa AF: 0.676 Hom.: 53105

Bravo AF: 0.722

Asia WGS AF: 0.883 AC: 3072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 15, 2022

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4684968; hg19: chr3-13670776; COSMIC: COSV108091480; COSMIC: COSV108091480;