rs376194507

Positions:

• chr5-128350879-C-G
• chr5-128350879-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001999.4(FBN2):​c.2801G>C​(p.Arg934Pro) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28302622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.2801G>C	p.Arg934Pro	missense_variant	21/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.2648G>C	p.Arg883Pro	missense_variant	20/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2801G>C	p.Arg934Pro	missense_variant	21/65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.2702G>C	p.Arg901Pro	missense_variant	20/33	2		ENSP00000425596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.39	T;.;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D;.;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-0.21	N;.;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.40	.;.;.;T
Polyphen		0.0010	B;.;B;B
Vest4		0.23
MutPred		0.65		Gain of catalytic residue at R934 (P = 0.054);.;Gain of catalytic residue at R934 (P = 0.054);.;
MVP		0.29
MPC		0.34
ClinPred		0.26	T
GERP RS		3.7
Varity_R		0.24
gMVP		0.68

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: rs376194507; hg19: chr5-127686571;