NM_001999.4:c.5823T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001999.4(FBN2):c.5823T>C(p.His1941His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 1,607,754 control chromosomes in the GnomAD database, including 8,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.094 ( 769 hom., cov: 32)

Exomes 𝑓: 0.10 ( 7666 hom. )

Consequence

FBN2
NM_001999.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.30

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

congenital contractural arachnodactyly
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
carpal tunnel syndrome
Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
macular degeneration, early-onset
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 5-128303067-A-G is Benign according to our data. Variant chr5-128303067-A-G is described in ClinVar as Benign. ClinVar VariationId is 129044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0999 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.5823T>C	p.His1941His	synonymous_variant	Exon 46 of 65	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.5670T>C	p.His1890His	synonymous_variant	Exon 45 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.5823T>C	p.His1941His	synonymous_variant	Exon 46 of 65	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000703783.1 link	n.2607T>C		non_coding_transcript_exon_variant	Exon 21 of 38
FBN2	ENST00000703785.1 link	n.2526T>C		non_coding_transcript_exon_variant	Exon 20 of 27

Frequencies

GnomAD3 genomes

AF:

0.0946

AC:

14377

AN:

152054

Hom.:

768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0795

Gnomad ASJ

AF:

0.0793

Gnomad EAS

AF:

0.0600

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.0643

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0885

GnomAD2 exomes

AF:

0.0937

AC:

23553

AN:

251308

AF XY:

0.0944

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.0918

Gnomad ASJ exome

AF:

0.0831

Gnomad EAS exome

AF:

0.0569

Gnomad FIN exome

AF:

0.0730

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0922

GnomAD4 exome

AF:

0.100

AC:

146194

AN:

1455582

Hom.:

7666

Cov.:

AF XY:

0.101

AC XY:

73124

AN XY:

724560

show subpopulations

African (AFR)

AF:

0.0978

AC:

3263

AN:

33348

American (AMR)

AF:

0.0888

AC:

3971

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0790

AC:

2061

AN:

26086

East Asian (EAS)

AF:

0.0614

AC:

2435

AN:

39640

South Asian (SAS)

AF:

0.106

AC:

9119

AN:

86132

European-Finnish (FIN)

AF:

0.0702

AC:

3748

AN:

53366

Middle Eastern (MID)

AF:

0.122

AC:

700

AN:

5750

European-Non Finnish (NFE)

AF:

0.104

AC:

114872

AN:

1106336

Other (OTH)

AF:

0.100

AC:

6025

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

5664

11327

16991

22654

28318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4182

8364

12546

16728

20910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0945

AC:

14378

AN:

152172

Hom.:

769

Cov.:

AF XY:

0.0918

AC XY:

6827

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.101

AC:

4189

AN:

41532

American (AMR)

AF:

0.0795

AC:

1214

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0793

AC:

275

AN:

3468

East Asian (EAS)

AF:

0.0594

AC:

307

AN:

5172

South Asian (SAS)

AF:

0.108

AC:

518

AN:

4816

European-Finnish (FIN)

AF:

0.0643

AC:

681

AN:

10584

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6919

AN:

68002

Other (OTH)

AF:

0.0881

AC:

186

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

655

1310

1966

2621

3276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0982

Hom.:

1075

Bravo

AF:

0.0953

Asia WGS

AF:

0.0740

AC:

261

AN:

3478

EpiCase

AF:

0.0984

EpiControl

AF:

0.0978

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His1941His in exon 46 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 10.6% (466/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11955288). -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2012

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 22, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The FBN2 c.5823T>C (p.His1941His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. 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 0.0948795 (11503/121238 control chromosomes [584 homozygotes]), which is approximately 75904 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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital contractural arachnodactyly

Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Nov 19, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

4.4

(source)

DANN

Benign

0.49

PhyloP100

1.3

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over