chr5-128276085-G-A

Variant names:

• chr5-128276085-G-A
• rs797045574
• NM_001999.4:c.7547C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001999.4(FBN2):​c.7547C>T​(p.Ser2516Leu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7547C>T	p.Ser2516Leu	missense_variant	Exon 59 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.7394C>T	p.Ser2465Leu	missense_variant	Exon 58 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7547C>T	p.Ser2516Leu	missense_variant	Exon 59 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.4331C>T		non_coding_transcript_exon_variant	Exon 34 of 38

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.80	N;.;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;.;D
REVEL	Pathogenic	0.81
Sift	Benign	0.072	T;.;T
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.47		Gain of catalytic residue at S2516 (P = 0.0011);.;Gain of catalytic residue at S2516 (P = 0.0011);
MVP		0.89
MPC		0.76
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.32
gMVP		0.64

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: rs797045574; hg19: chr5-127611777; COSMIC: COSV52514438;