Variant rs780589159 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM2PP2PP3_ModerateBP6_Moderate

The NM_001999.4(FBN2):c.1961G>C(p.Arg654Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R654H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FBN2
NM_001999.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.84

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

BP6

Variant 5-128376742-C-G is Benign according to our data. Variant chr5-128376742-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 435178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4 linkuse as main transcript	c.1961G>C	p.Arg654Pro	missense_variant	14/65	ENST00000262464.9
FBN2	XM_017009228.3 linkuse as main transcript	c.1808G>C	p.Arg603Pro	missense_variant	13/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9 linkuse as main transcript	c.1961G>C	p.Arg654Pro	missense_variant	14/65	1	NM_001999.4	P1	P35556-1
FBN2	ENST00000508989.5 linkuse as main transcript	c.1862G>C	p.Arg621Pro	missense_variant	13/33	2
FBN2	ENST00000511489.1 linkuse as main transcript	n.182G>C		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;.;.;T

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.6

L;.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.2

D;.;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0070

D;.;D;D

Sift4G

Benign

0.17

.;.;.;T

Polyphen

1.0

D;.;D;D

Vest4

0.97

MutPred

0.69

Loss of catalytic residue at R654 (P = 0.0103);.;Loss of catalytic residue at R654 (P = 0.0103);.;

MVP

0.92

MPC

1.0

ClinPred

0.82

GERP RS

4.6

Varity_R

0.88

gMVP

0.92

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