chr5-128261826-G-A

Position:

• chr5-128261826-G-A

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.8274C>T​(p.Ser2758=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,570 control chromosomes in the GnomAD database, including 11,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1447 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9795 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.364

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=-0.48).
• BP6: Variant 5-128261826-G-A is Benign according to our data. Variant chr5-128261826-G-A is described in ClinVar as [Benign]. Clinvar id is 129053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128261826-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.8274C>T	p.Ser2758=	synonymous_variant	64/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.8121C>T	p.Ser2707=	synonymous_variant	63/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.8274C>T	p.Ser2758=	synonymous_variant	64/65	1	NM_001999.4	ENSP00000262464	P1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19569 AN: 152020 Hom.: 1448 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0905

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.0401

Gnomad SAS AF: 0.0692

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.102 AC: 25633 AN: 251166 Hom.: 1575 AF XY: 0.100 AC XY: 13637 AN XY: 135706

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.0516

Gnomad EAS exome AF: 0.0283

Gnomad SAS exome AF: 0.0643

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.112 AC: 163982 AN: 1461432 Hom.: 9795 Cov.: 32 AF XY: 0.111 AC XY: 80521 AN XY: 727054

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0730

Gnomad4 ASJ exome AF: 0.0552

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.0644

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.129 AC: 19593 AN: 152138 Hom.: 1447 Cov.: 32 AF XY: 0.128 AC XY: 9533 AN XY: 74366

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0904

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.0404

Gnomad4 SAS AF: 0.0693

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.114

Alfa AF: 0.119 Hom.: 567

Bravo AF: 0.125

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ser2758Ser in exon 64 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 17.3% (764/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10070365). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 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. -

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
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 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.8274C>T (p.Ser2758Ser) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts no significant effect on ESE sites caused by the variant. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.1042542 (12655/121386 control chromosomes [778 homozygotes]), which is approximately 83403 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. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.6
DANN	Benign	0.53

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: rs10070365; hg19: chr5-127597518; COSMIC: COSV52501113;