rs1461140915

Variant names:

• chr5-128280218-G-A
• rs1461140915
• NM_001999.4:c.7112C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128280218-G-A
• chr5-128280218-G-C

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.7112C>T​(p.Ser2371Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.26
• 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=0.11118069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.7112C>T	p.Ser2371Leu	missense_variant	Exon 56 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6959C>T	p.Ser2320Leu	missense_variant	Exon 55 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.7112C>T	p.Ser2371Leu	missense_variant	Exon 56 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3896C>T		non_coding_transcript_exon_variant	Exon 31 of 38

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250940 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.60	N;.;N
PhyloP100		5.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.83	T;.;T
Polyphen		0.0070	B;.;B
Vest4		0.22
MutPred		0.53		Loss of disorder (P = 0.0292);.;Loss of disorder (P = 0.0292);
MVP		0.32
MPC		0.21
ClinPred		0.32	T
GERP RS		4.1
Varity_R		0.096
gMVP		0.80
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs1461140915; hg19: chr5-127615910; COSMIC: COSV52509999;