rs1450302477

Variant names:

• chr5-128289888-G-A
• rs1450302477
• NM_001999.4:c.6505C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128289888-G-A
• chr5-128289888-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001999.4(FBN2):​c.6505C>T​(p.Arg2169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,576,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2169H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.68
• Publications: 2 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• carpal tunnel syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 5-128289888-G-A is Benign according to our data. Variant chr5-128289888-G-A is described in ClinVar as Benign. ClinVar VariationId is 528401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 13 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	NM_001999.4	MANE Select	c.6505C>T	p.Arg2169Cys	missense	Exon 51 of 65	NP_001990.2	P35556-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.6505C>T	p.Arg2169Cys	missense	Exon 51 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.6406C>T	p.Arg2136Cys	missense	Exon 50 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.6352C>T	p.Arg2118Cys	missense	Exon 50 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250666 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000913 AC: 13 AN: 1424588 Hom.: 0 Cov.: 26 AF XY: 0.00000562 AC XY: 4 AN XY: 711230

African (AFR) AF: 0.0000610 AC: 2 AN: 32792

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 85324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.00000927 AC: 10 AN: 1078404

Other (OTH) AF: 0.00 AC: 0 AN: 59042

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital contractural arachnodactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.052	D
MutationAssessor	Benign	-1.2	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.58
Sift	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.48		Loss of disorder (P = 0.0894)
MVP		0.54
MPC		0.92
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.66
Mutation Taster		=58/42	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: rs1450302477; hg19: chr5-127625580; COSMIC: COSV105107662;