rs2279582

Positions:

• chr5-128335540-G-A

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.3762C>T​(p.Asp1254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,613,926 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (61 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.09

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=-0.39).
• BP6: Variant 5-128335540-G-A is Benign according to our data. Variant chr5-128335540-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128335540-G-A is described in Lovd as [Benign]. Variant chr5-128335540-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00585 (891/152328) while in subpopulation EAS AF= 0.0209 (108/5178). AF 95% confidence interval is 0.0177. There are 7 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 891 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.3762C>T	p.Asp1254=	synonymous_variant	29/65	ENST00000262464.9
FBN2	XM_017009228.3	c.3609C>T	p.Asp1203=	synonymous_variant	28/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.3762C>T	p.Asp1254=	synonymous_variant	29/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152210 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00719 AC: 1808 AN: 251290 Hom.: 19 AF XY: 0.00712 AC XY: 967 AN XY: 135804

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0207

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.00649

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00711 AC: 10386 AN: 1461598 Hom.: 61 Cov.: 33 AF XY: 0.00682 AC XY: 4962 AN XY: 727118

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.0191

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.00691

Gnomad4 OTH exome AF: 0.00722

GnomAD4 genome AF: 0.00585 AC: 891 AN: 152328 Hom.: 7 Cov.: 32 AF XY: 0.00628 AC XY: 468 AN XY: 74490

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0190

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00578 Hom.: 2

Bravo AF: 0.00485

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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. -

Connective tissue disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Nov 01, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2015

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

Nov 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.1
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2279582; hg19: chr5-127671232; COSMIC: COSV52527850;