5-128345559-C-T

Position:

• chr5-128345559-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001999.4(FBN2):​c.3015G>A​(p.Leu1005=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,612,682 control chromosomes in the GnomAD database, including 602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (34 hom., cov: 32)
  • Exomes 𝑓: 0.025 (568 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.38

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 5-128345559-C-T is Benign according to our data. Variant chr5-128345559-C-T is described in ClinVar as [Benign]. Clinvar id is 129040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128345559-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0181 (2727/150952) while in subpopulation AMR AF= 0.0338 (514/15222). AF 95% confidence interval is 0.0314. There are 34 homozygotes in gnomad4. There are 1264 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2727 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3015G>A	p.Leu1005=	synonymous_variant	24/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.2862G>A	p.Leu954=	synonymous_variant	23/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3015G>A	p.Leu1005=	synonymous_variant	24/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000508989.5	c.2916G>A	p.Leu972=	synonymous_variant	23/33	2		ENSP00000425596

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2726 AN: 150834 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00706

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.00984

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0159 AC: 4006 AN: 251382 Hom.: 64 AF XY: 0.0158 AC XY: 2151 AN XY: 135864

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.00874

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0247 AC: 36163 AN: 1461730 Hom.: 568 Cov.: 32 AF XY: 0.0240 AC XY: 17426 AN XY: 727184

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.00335

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0181 AC: 2727 AN: 150952 Hom.: 34 Cov.: 32 AF XY: 0.0171 AC XY: 1264 AN XY: 73778

Gnomad4 AFR AF: 0.00704

Gnomad4 AMR AF: 0.0338

Gnomad4 ASJ AF: 0.00984

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.0265

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.0214 Hom.: 33

Bravo AF: 0.0204

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0265

EpiControl AF: 0.0258

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Leu1005Leu in exon 24 of FBN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.9% (247/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs28763946). -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2013	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. -

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2017	Variant summary: The FBN2 c.3015G>A (p.Leu1005Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1779/121186 control chromosomes (20 homozygotes) at a frequency of 0.0146799, which is approximately 11744 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	4.6
DANN	Benign	0.75

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: rs28763946; hg19: chr5-127681251;