NM_001999.4:c.2620A>G

Variant names:

• chr5-128357330-T-C
• rs1297639505
• NM_001999.4:c.2620A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001999.4(FBN2):​c.2620A>G​(p.Asn874Asp) 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. 17/22 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. N874H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23636141).

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.2620A>G	p.Asn874Asp	missense	Exon 20 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.2620A>G	p.Asn874Asp	missense	Exon 20 of 65	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.2521A>G	p.Asn841Asp	missense	Exon 19 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.2467A>G	p.Asn823Asp	missense	Exon 19 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.35	N
PhyloP100		-0.12
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.20
Sift	Benign	0.62	T
Sift4G	Benign	0.40	T
Polyphen		0.033	B
Vest4		0.29
MutPred		0.54		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.37
MPC		0.32
ClinPred		0.19	T
GERP RS		2.6
Varity_R		0.060
gMVP		0.41
Mutation Taster		=94/6	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: rs1297639505; hg19: chr5-127693022; COSMIC: COSV105867346;