Variant rs56131649 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000262464.9(FBN2):c.6511+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,475,690 control chromosomes in the GnomAD database, including 20,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1909 hom., cov: 32)

Exomes 𝑓: 0.16 ( 18392 hom. )

Consequence

FBN2
ENST00000262464.9 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.37

Variant links:

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]

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-128289867-T-C is Benign according to our data. Variant chr5-128289867-T-C is described in ClinVar as [Benign]. Clinvar id is 137345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128289867-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.6511+15A>G		intron_variant		ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3 linkuse as main transcript	c.6358+15A>G		intron_variant			XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.6511+15A>G	intron_variant	1	NM_001999.4	ENSP00000262464	P1	P35556-1
FBN2	ENST00000703783.1 linkuse as main transcript	n.3295+15A>G	intron_variant, non_coding_transcript_variant
FBN2	ENST00000703785.1 linkuse as main transcript	n.3214+15A>G	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21759

AN:

151968

Hom.:

1901

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0532

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.164

Gnomad OTH

AF:

0.145

GnomAD3 exomes

AF:

0.179

AC:

44026

AN:

246426

Hom.:

4584

AF XY:

0.176

AC XY:

23478

AN XY:

133322

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.156

Gnomad SAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.162

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.160

AC:

212230

AN:

1323604

Hom.:

18392

Cov.:

AF XY:

0.161

AC XY:

107242

AN XY:

666080

show subpopulations

Gnomad4 AFR exome

AF:

0.0483

Gnomad4 AMR exome

AF:

0.288

Gnomad4 ASJ exome

AF:

0.119

Gnomad4 EAS exome

AF:

0.180

Gnomad4 SAS exome

AF:

0.177

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.155

Gnomad4 OTH exome

AF:

0.149

GnomAD4 genome

AF:

0.143

AC:

21780

AN:

152086

Hom.:

1909

Cov.:

AF XY:

0.148

AC XY:

10968

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0531

Gnomad4 AMR

AF:

0.227

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.167

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.164

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.149

Hom.:

543

Bravo

AF:

0.137

Asia WGS

AF:

0.228

AC:

791

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	6511+15A>G in intron 51 of FBN2: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 16.1% (1383/8594) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs56131649). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 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	PreventionGenetics, part of Exact Sciences	-	- -

Congenital contractural arachnodactyly

Benign:2

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:1

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.6511+15A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 20207/102662 control chromosomes (2001 homozygotes) at a frequency of 0.1968, which is approximately 157463 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.020

DANN

Benign

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over