chr5-128349358-C-A

Variant names:

• chr5-128349358-C-A
• rs774483323
• NM_001999.4:c.2978G>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.2978G>T​(p.Arg993Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84

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, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.2978G>T	p.Arg993Leu	missense_variant	Exon 23 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.2825G>T	p.Arg942Leu	missense_variant	Exon 22 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2978G>T	p.Arg993Leu	missense_variant	Exon 23 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.2879G>T	p.Arg960Leu	missense_variant	Exon 22 of 33	2		ENSP00000425596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;.;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.5	L;.;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D;.;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0070	D;.;D;T
Sift4G	Benign	0.52	.;.;.;T
Polyphen		0.99	D;.;D;D
Vest4		0.87
MutPred		0.65		Gain of catalytic residue at D989 (P = 0.1295);.;Gain of catalytic residue at D989 (P = 0.1295);.;
MVP		0.89
MPC		0.31
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.39
gMVP		0.71

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: rs774483323; hg19: chr5-127685050;