rs775905979

Variant names:

• chr5-128280272-C-T
• rs775905979
• NM_001999.4:c.7058G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001999.4(FBN2):​c.7058G>A​(p.Arg2353His) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,611,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2353C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.54
• 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: 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 -5 ACMG points.

• BP6: Variant 5-128280272-C-T is Benign according to our data. Variant chr5-128280272-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 411818.
• BS2: High AC in GnomAdExome4 at 14 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.7058G>A	p.Arg2353His	missense	Exon 56 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.7058G>A	p.Arg2353His	missense	Exon 56 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.6959G>A	p.Arg2320His	missense	Exon 55 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.6905G>A	p.Arg2302His	missense	Exon 55 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250820 AF XY: 0.0000221

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458818 Hom.: 0 Cov.: 28 AF XY: 0.00000964 AC XY: 7 AN XY: 725884

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1109482

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital contractural arachnodactyly (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.66
Sift	Benign	0.15	T
Polyphen		0.74	P
Vest4		0.27
MutPred		0.67		Loss of disorder (P = 0.0716)
MVP		0.97
MPC		0.38
ClinPred		0.78	D
GERP RS		4.1
Varity_R		0.089
gMVP		0.73
Mutation Taster		=51/49	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: rs775905979; hg19: chr5-127615964;