5-128336002-C-G

Variant names:

• chr5-128336002-C-G
• rs142185964
• NM_001999.4:c.3710G>C

Variant summary

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

The NM_001999.4(FBN2):​c.3710G>C​(p.Arg1237Pro) 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. 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: 3.33

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, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.3710G>C	p.Arg1237Pro	missense_variant	Exon 28 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.3557G>C	p.Arg1186Pro	missense_variant	Exon 27 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.3710G>C	p.Arg1237Pro	missense_variant	Exon 28 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;.;T;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	2.0	M;.;M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.7	D;.;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.011	D;.;D;D;D
Sift4G	Benign	0.12	.;.;.;T;T
Polyphen		1.0	D;.;D;.;D
Vest4		0.75
MutPred		0.56		Gain of glycosylation at T1234 (P = 0.0155);.;Gain of glycosylation at T1234 (P = 0.0155);.;.;
MVP		0.91
MPC		0.40
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.92

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: rs142185964; hg19: chr5-127671694;