chr5-128261729-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001999.4(FBN2):c.8364+7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,014 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

FBN2
NM_001999.4 splice_region, intron

Scores

Splicing: ADA: 0.00001784

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.0910

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=-0.79).

BP6

Variant 5-128261729-T-A is Benign according to our data. Variant chr5-128261729-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 137355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128261729-T-A is described in Lovd as [Benign]. Variant chr5-128261729-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00119 (182/152378) while in subpopulation NFE AF= 0.00218 (148/68040). AF 95% confidence interval is 0.00189. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.8364+7A>T		splice_region_variant, intron_variant	Intron 64 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.8211+7A>T		splice_region_variant, intron_variant	Intron 63 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9 link	c.8364+7A>T		splice_region_variant, intron_variant	Intron 64 of 64	1	NM_001999.4	ENSP00000262464.4		P35556-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00217

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00107

AC:

268

AN:

251120

Hom.:

AF XY:

0.00110

AC XY:

149

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00167

AC:

2435

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1145

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00203

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00119

AC:

182

AN:

152378

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.00113

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly

Benign:5

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 21, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4

Mar 30, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Oct 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FBN2: BP4, BS1 -

Connective tissue disorder

Benign:2

Nov 03, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2018

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Mar 01, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.7

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0

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