chr5-128537452-G-A

Variant names:

• chr5-128537452-G-A
• rs1060503509
• NM_001999.4:c.152C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001999.4(FBN2):​c.152C>T​(p.Thr51Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. T51R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045933723).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001999.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.152C>T	p.Thr51Ile	missense	Exon 1 of 65	NP_001990.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.152C>T	p.Thr51Ile	missense	Exon 1 of 65	ENSP00000262464.4
	FBN2	ENST00000502468.5	TSL:1	c.152C>T	p.Thr51Ile	missense	Exon 1 of 8	ENSP00000424753.1
	FBN2	ENST00000508989.5	TSL:2	c.152C>T	p.Thr51Ile	missense	Exon 1 of 33	ENSP00000425596.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454952 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723404

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110060

Other (OTH) AF: 0.00 AC: 0 AN: 60116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.3
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.42	N
PhyloP100		0.070
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.095
Sift	Benign	0.077	T
Sift4G	Benign	0.22	T
Polyphen		0.0030	B
Vest4		0.14
MutPred		0.24		Loss of phosphorylation at T51 (P = 0.0137)
MVP		0.24
MPC		0.25
ClinPred		0.058	T
GERP RS		0.52
PromoterAI		-0.013	Neutral
Varity_R		0.038
gMVP		0.44
Mutation Taster		=96/4	polymorphism

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: rs1060503509; hg19: chr5-127873145;