Genetic Variant NM_001999.4:c.2625T>C (chr5-128357325-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001999.4(FBN2):c.2625T>C(p.Cys875Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

FBN2
NM_001999.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.57

Publications

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

FBN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-128357325-A-G is Benign according to our data. Variant chr5-128357325-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213224.

BP7

Synonymous conserved (PhyloP=1.57 with no splicing effect.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.2625T>C	p.Cys875Cys	synonymous	Exon 20 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN2	ENST00000262464.9	TSL:1 MANE Select	c.2625T>C	p.Cys875Cys	synonymous	Exon 20 of 65	ENSP00000262464.4	P35556-1
FBN2	ENST00000939405.1		c.2526T>C	p.Cys842Cys	synonymous	Exon 19 of 64	ENSP00000609464.1
FBN2	ENST00000939404.1		c.2472T>C	p.Cys824Cys	synonymous	Exon 19 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000636

AC:

AN:

251388

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000160

AC:

234

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000192

AC:

213

AN:

1111848

Other (OTH)

AF:

0.000265

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000112

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000189

Hom.:

Bravo

AF:

0.0000907

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital contractural arachnodactyly (2)

not provided (2)

not specified (2)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.8

(source)

DANN

Benign

0.58

PhyloP100

1.6

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over