rs368384428

Variant names:

• chr5-128305079-C-A
• rs368384428
• NM_001999.4:c.5678G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128305079-C-A
• chr5-128305079-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001999.4(FBN2):​c.5678G>T​(p.Arg1893Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1893H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.16
• Publications: 0 publications found

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]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.5678G>T	p.Arg1893Leu	missense_variant	Exon 45 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.5525G>T	p.Arg1842Leu	missense_variant	Exon 44 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.5678G>T	p.Arg1893Leu	missense_variant	Exon 45 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2462G>T		non_coding_transcript_exon_variant	Exon 20 of 38
FBN2	ENST00000703785.1	n.2381G>T		non_coding_transcript_exon_variant	Exon 19 of 27

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150548 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454048 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723516

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 44282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105904

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 150548 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73504

African (AFR) AF: 0.00 AC: 0 AN: 40084

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2082

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	0.15	N;.;N
PhyloP100		6.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Pathogenic	0.65
Sift	Benign	0.43	T;.;T
Polyphen		0.98	D;.;D
Vest4		0.86
MutPred		0.50		Loss of solvent accessibility (P = 0.1922);.;Loss of solvent accessibility (P = 0.1922);
MVP		0.91
MPC		0.96
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.24
gMVP		0.61
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs368384428; hg19: chr5-127640771;