rs73348287

Variant names:

• chr5-128537421-G-C
• rs73348287
• NM_001999.4:c.183C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.183C>G​(p.Pro61Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,609,328 control chromosomes in the GnomAD database, including 6,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (925 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5460 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.54
• Publications: 10 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-128537421-G-C is Benign according to our data. Variant chr5-128537421-G-C is described in ClinVar as Benign. ClinVar VariationId is 129036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

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.183C>G	p.Pro61Pro	synonymous	Exon 1 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.183C>G	p.Pro61Pro	synonymous	Exon 1 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000502468.5	TSL:1	c.183C>G	p.Pro61Pro	synonymous	Exon 1 of 8	ENSP00000424753.1	E9PHW4
	FBN2	ENST00000939405.1		c.183C>G	p.Pro61Pro	synonymous	Exon 1 of 64	ENSP00000609464.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15692 AN: 152092 Hom.: 921 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.00543

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0850

Gnomad OTH AF: 0.0872

GnomAD2 exomes AF: 0.0789 AC: 18852 AN: 239022 AF XY: 0.0783

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.0529

Gnomad ASJ exome AF: 0.0737

Gnomad EAS exome AF: 0.00178

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0828

GnomAD4 exome AF: 0.0833 AC: 121307 AN: 1457122 Hom.: 5460 Cov.: 33 AF XY: 0.0831 AC XY: 60254 AN XY: 724674

African (AFR) AF: 0.167 AC: 5595 AN: 33458

American (AMR) AF: 0.0545 AC: 2425 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.0731 AC: 1902 AN: 26014

East Asian (EAS) AF: 0.0110 AC: 438 AN: 39658

South Asian (SAS) AF: 0.0850 AC: 7274 AN: 85528

European-Finnish (FIN) AF: 0.0785 AC: 3993 AN: 50890

Middle Eastern (MID) AF: 0.0765 AC: 441 AN: 5762

European-Non Finnish (NFE) AF: 0.0849 AC: 94362 AN: 1111082

Other (OTH) AF: 0.0810 AC: 4877 AN: 60218

GnomAD4 genome AF: 0.103 AC: 15722 AN: 152206 Hom.: 925 Cov.: 33 AF XY: 0.101 AC XY: 7518 AN XY: 74418

African (AFR) AF: 0.170 AC: 7058 AN: 41542

American (AMR) AF: 0.0648 AC: 991 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 281 AN: 3472

East Asian (EAS) AF: 0.00545 AC: 28 AN: 5142

South Asian (SAS) AF: 0.0773 AC: 373 AN: 4826

European-Finnish (FIN) AF: 0.0869 AC: 921 AN: 10604

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0850 AC: 5780 AN: 68006

Other (OTH) AF: 0.0858 AC: 181 AN: 2110

Alfa AF: 0.0877 Hom.: 211

Bravo AF: 0.103

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Congenital contractural arachnodactyly (4)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-1.5
PromoterAI		0.016	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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: rs73348287; hg19: chr5-127873114;