rs1479056828

Variant names:

• chr5-128334762-A-C
• rs1479056828
• NM_001999.4:c.4056T>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128334762-A-C
• chr5-128334762-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001999.4(FBN2):​c.4056T>G​(p.Cys1352Trp) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1352S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.122
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-128334763-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 930425.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 5-128334762-A-C is Pathogenic according to our data. Variant chr5-128334762-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 528417.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.4056T>G	p.Cys1352Trp	missense	Exon 31 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.4056T>G	p.Cys1352Trp	missense	Exon 31 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.3957T>G	p.Cys1319Trp	missense	Exon 30 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.3903T>G	p.Cys1301Trp	missense	Exon 30 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital contractural arachnodactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		0.12
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of sheet (P = 0.1158)
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		-0.39
Varity_R		0.89
gMVP		0.99
Mutation Taster		=9/91	disease causing

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: rs1479056828; hg19: chr5-127670454;