5-128335543-A-C

Position:

• chr5-128335543-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001999.4(FBN2):​c.3759T>G​(p.Cys1253Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.194

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain EGF-like 19; calcium-binding (size 40) in uniprot entity FBN2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001999.4
• 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, 0.994
• PP5: Variant 5-128335543-A-C is Pathogenic according to our data. Variant chr5-128335543-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 527.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3759T>G	p.Cys1253Trp	missense_variant	29/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3606T>G	p.Cys1202Trp	missense_variant	28/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3759T>G	p.Cys1253Trp	missense_variant	29/65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;D;T;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;.;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.8	H;.;H;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-9.8	D;.;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.97
MutPred		0.99		Loss of disorder (P = 0.0207);.;Loss of disorder (P = 0.0207);.;.;
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		-1.1
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28931602; hg19: chr5-127671235;