rs745759959

chr5-128305525-T-Achr5-128305525-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001999.4(FBN2):c.5660A>T(p.Asn1887Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1887S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.34445632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.5660A>T	p.Asn1887Ile	missense_variant	44/65	ENST00000262464.9
FBN2	XM_017009228.3	c.5507A>T	p.Asn1836Ile	missense_variant	43/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.5660A>T	p.Asn1887Ile	missense_variant	44/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.2444A>T		non_coding_transcript_exon_variant	19/38
FBN2	ENST00000703785.1	n.2363A>T		non_coding_transcript_exon_variant	18/27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251338 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727184

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;.;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.36	T;.;.
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Uncertain	0.60
Sift	Benign	0.17	T;.;T
Polyphen		0.62	P;.;P
Vest4		0.44
MutPred		0.75		Loss of disorder (P = 0.0544);.;Loss of disorder (P = 0.0544);
MVP		0.60
MPC		0.57
ClinPred		0.92	D
GERP RS		4.1
Varity_R		0.25
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745759959; hg19: chr5-127641217;