Genetic Variant NM_001999.4:c.952+11369C>G (chr5-128435112-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001999.4(FBN2):c.952+11369C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 152,048 control chromosomes in the GnomAD database, including 1,026 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.098 ( 1026 hom., cov: 31)

Consequence

FBN2
NM_001999.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.687

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4 link	c.952+11369C>G		intron_variant	Intron 7 of 64	ENST00000262464.9	NP_001990.2	P35556-1
FBN2	XM_017009228.3 link	c.952+11369C>G		intron_variant	Intron 7 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FBN2	ENST00000262464.9 link	c.952+11369C>G	intron_variant	Intron 7 of 64	1	NM_001999.4	ENSP00000262464.4	P35556-1
FBN2	ENST00000508989.5 link	c.853+11369C>G	intron_variant	Intron 6 of 32	2		ENSP00000425596.1	D6RJI3
FBN2	ENST00000508053.6 link	c.952+11369C>G	intron_variant	Intron 13 of 14	5		ENSP00000424571.2	A0A9H4AZX0
FBN2	ENST00000703787.1 link	n.659+11369C>G	intron_variant	Intron 6 of 9

Frequencies

GnomAD3 genomes

AF:

0.0980

AC:

14883

AN:

151930

Hom.:

1022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0436

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.0615

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0555

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.133

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0979

AC:

14893

AN:

152048

Hom.:

1026

Cov.:

AF XY:

0.0991

AC XY:

7364

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0434

AC:

1800

AN:

41508

American (AMR)

AF:

0.238

AC:

3632

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

434

AN:

3472

East Asian (EAS)

AF:

0.0621

AC:

320

AN:

5156

South Asian (SAS)

AF:

0.108

AC:

523

AN:

4826

European-Finnish (FIN)

AF:

0.0555

AC:

587

AN:

10576

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7163

AN:

67952

Other (OTH)

AF:

0.131

AC:

276

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

668

1337

2005

2674

3342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0947

Hom.:

121

Bravo

AF:

0.113

Asia WGS

AF:

0.0830

AC:

289

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.69

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over