5-128335170-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_001999.4(FBN2):c.3973G>A(p.Asp1325Asn) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
FBN2
NM_001999.4 missense, splice_region
NM_001999.4 missense, splice_region
Scores
14
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.91
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_001999.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, FBN2
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 5-128335170-C-T is Pathogenic according to our data. Variant chr5-128335170-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446528.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 | c.3973G>A | p.Asp1325Asn | missense_variant, splice_region_variant | 30/65 | ENST00000262464.9 | |
FBN2 | XM_017009228.3 | c.3820G>A | p.Asp1274Asn | missense_variant, splice_region_variant | 29/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN2 | ENST00000262464.9 | c.3973G>A | p.Asp1325Asn | missense_variant, splice_region_variant | 30/65 | 1 | NM_001999.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital contractural arachnodactyly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | provider interpretation | Medical Genetics Clinic, Mersin Women and Children Hospital | Nov 28, 2017 | According to Standards and guidelines for the interpretation of sequence results by ACMG (Richards S and Committee 2015) the variant is classified as likely pathogenic [(ii) and (iii); (PS2, PM2, PP2, PP3, PP4)]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D;T
Polyphen
D;.;D;.;D
Vest4
MutPred
Loss of ubiquitination at K1321 (P = 0.0584);.;Loss of ubiquitination at K1321 (P = 0.0584);.;.;
MVP
MPC
0.84
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at