rs35346129

Variant names:

• chr5-128305875-G-A
• rs35346129
• NM_001999.4:c.5496C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128305875-G-A
• chr5-128305875-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001999.4(FBN2):​c.5496C>T​(p.Arg1832Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,902 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (25 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 1.21
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 5-128305875-G-A is Benign according to our data. Variant chr5-128305875-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137341.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00371 (565/152276) while in subpopulation NFE AF = 0.00617 (420/68022). AF 95% confidence interval is 0.00569. There are 5 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 565 AD 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.5496C>T	p.Arg1832Arg	synonymous	Exon 43 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.5496C>T	p.Arg1832Arg	synonymous	Exon 43 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.5397C>T	p.Arg1799Arg	synonymous	Exon 42 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.5343C>T	p.Arg1781Arg	synonymous	Exon 42 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152158 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00915

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00393 AC: 987 AN: 251280 AF XY: 0.00396

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00961

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00548 AC: 8010 AN: 1461626 Hom.: 25 Cov.: 31 AF XY: 0.00524 AC XY: 3808 AN XY: 727130

African (AFR) AF: 0.000717 AC: 24 AN: 33474

American (AMR) AF: 0.000649 AC: 29 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00985 AC: 526 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00651 AC: 7234 AN: 1111798

Other (OTH) AF: 0.00318 AC: 192 AN: 60384

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152276 Hom.: 5 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74454

African (AFR) AF: 0.000794 AC: 33 AN: 41558

American (AMR) AF: 0.000785 AC: 12 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00915 AC: 97 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00617 AC: 420 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00478 Hom.: 4

Bravo AF: 0.00305

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not specified (7)
-	-	3	not provided (3)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	Connective tissue disorder (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.6
DANN	Benign	0.66
PhyloP100		1.2
Mutation Taster		=100/0	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: rs35346129; hg19: chr5-127641567;