5-128537421-G-C

Position:

• chr5-128537421-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.183C>G​(p.Pro61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,609,328 control chromosomes in the GnomAD database, including 6,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (925 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5460 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.54

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-128537421-G-C is Benign according to our data. Variant chr5-128537421-G-C is described in ClinVar as [Benign]. Clinvar id is 129036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128537421-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.183C>G	p.Pro61=	synonymous_variant	1/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.183C>G	p.Pro61=	synonymous_variant	1/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.183C>G	p.Pro61=	synonymous_variant	1/65	1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15692 AN: 152092 Hom.: 921 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.00543

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0850

Gnomad OTH AF: 0.0872

GnomAD3 exomes AF: 0.0789 AC: 18852 AN: 239022 Hom.: 929 AF XY: 0.0783 AC XY: 10195 AN XY: 130240

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0529

Gnomad ASJ exome AF: 0.0737

Gnomad EAS exome AF: 0.00178

Gnomad SAS exome AF: 0.0859

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0833 AC: 121307 AN: 1457122 Hom.: 5460 Cov.: 33 AF XY: 0.0831 AC XY: 60254 AN XY: 724674

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.0545

Gnomad4 ASJ exome AF: 0.0731

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.0850

Gnomad4 FIN exome AF: 0.0785

Gnomad4 NFE exome AF: 0.0849

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome AF: 0.103 AC: 15722 AN: 152206 Hom.: 925 Cov.: 33 AF XY: 0.101 AC XY: 7518 AN XY: 74418

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0648

Gnomad4 ASJ AF: 0.0809

Gnomad4 EAS AF: 0.00545

Gnomad4 SAS AF: 0.0773

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0850

Gnomad4 OTH AF: 0.0858

Alfa AF: 0.0877 Hom.: 211

Bravo AF: 0.103

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Pro61Pro in exon 1 of FBN2: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 17.0% (745/4394) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs73348287). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Congenital contractural arachnodactyly Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs73348287; hg19: chr5-127873114;