5-128408776-G-C

Variant names:

• chr5-128408776-G-C
• rs28763954
• NM_001999.4:c.976C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001999.4(FBN2):​c.976C>G​(p.Pro326Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P326S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.976C>G	p.Pro326Ala	missense_variant	Exon 8 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.976C>G	p.Pro326Ala	missense_variant	Exon 8 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.976C>G	p.Pro326Ala	missense_variant	Exon 8 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000508989.5	c.877C>G	p.Pro293Ala	missense_variant	Exon 7 of 33	2		ENSP00000425596.1
FBN2	ENST00000508053.6	c.976C>G	p.Pro326Ala	missense_variant	Exon 14 of 15	5		ENSP00000424571.2
FBN2	ENST00000703787.1	n.683C>G		non_coding_transcript_exon_variant	Exon 7 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;.;.;T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.3	M;.;M;.
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D;.;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.028	D;.;D;D
Sift4G	Uncertain	0.046	.;.;.;D
Polyphen		0.55	P;.;P;P
Vest4		0.45
MutPred		0.79		Loss of disorder (P = 0.0496);.;Loss of disorder (P = 0.0496);.;
MVP		0.73
MPC		0.24
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.27
gMVP		0.44
Mutation Taster		=71/29	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: rs28763954; hg19: chr5-127744469;