rs730882230

Variant names:

• chr5-128408688-C-T
• rs730882230
• NM_001999.4:c.1064G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 183327.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

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

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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;.
PhyloP100		7.3
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882230; hg19: chr5-127744381;