5-128408688-C-T

Position:

• chr5-128408688-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001999.4(FBN2):​c.1064G>A​(p.Gly355Asp) 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 pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.29

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 0.98
• PP5: Variant 5-128408688-C-T is Pathogenic according to our data. Variant chr5-128408688-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183327.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-128408688-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.1064G>A	p.Gly355Asp	missense_variant	8/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1064G>A	p.Gly355Asp	missense_variant	8/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.1064G>A	p.Gly355Asp	missense_variant	8/65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.965G>A	p.Gly322Asp	missense_variant	7/33	2		ENSP00000425596.1
FBN2	ENST00000508053.6	c.1064G>A	p.Gly355Asp	missense_variant	14/15	5		ENSP00000424571.2
FBN2	ENST00000703787.1	n.771G>A		non_coding_transcript_exon_variant	7/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neonatal death;C0917798:Cerebral ischemia;C1276035:Fetal akinesia deformation sequence 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;.;.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.5	M;.;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.3	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.017	D;.;D;D
Sift4G	Uncertain	0.021	.;.;.;D
Polyphen		1.0	D;.;D;D
Vest4		0.89
MutPred		0.88		Gain of catalytic residue at G355 (P = 0.081);.;Gain of catalytic residue at G355 (P = 0.081);.;
MVP		0.93
MPC		0.79
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.50
gMVP		0.73

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

Other links and lift over

dbSNP: rs730882230; hg19: chr5-127744381;