chr5-128335540-G-A

Variant names:

• chr5-128335540-G-A
• rs2279582
• NM_001999.4:c.3762C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001999.4(FBN2):​c.3762C>T​(p.Asp1254Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,613,926 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (61 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.09
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-128335540-G-A is Benign according to our data. Variant chr5-128335540-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00585 (891/152328) while in subpopulation EAS AF = 0.0209 (108/5178). AF 95% confidence interval is 0.0177. There are 7 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 891 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.3762C>T	p.Asp1254Asp	synonymous	Exon 29 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.3762C>T	p.Asp1254Asp	synonymous	Exon 29 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.3663C>T	p.Asp1221Asp	synonymous	Exon 28 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.3609C>T	p.Asp1203Asp	synonymous	Exon 28 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152210 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00719 AC: 1808 AN: 251290 AF XY: 0.00712

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0207

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.00649

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00711 AC: 10386 AN: 1461598 Hom.: 61 Cov.: 33 AF XY: 0.00682 AC XY: 4962 AN XY: 727118

African (AFR) AF: 0.00137 AC: 46 AN: 33470

American (AMR) AF: 0.00271 AC: 121 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26134

East Asian (EAS) AF: 0.0191 AC: 758 AN: 39700

South Asian (SAS) AF: 0.00218 AC: 188 AN: 86254

European-Finnish (FIN) AF: 0.0192 AC: 1028 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00691 AC: 7687 AN: 1111738

Other (OTH) AF: 0.00722 AC: 436 AN: 60390

GnomAD4 genome AF: 0.00585 AC: 891 AN: 152328 Hom.: 7 Cov.: 32 AF XY: 0.00628 AC XY: 468 AN XY: 74490

African (AFR) AF: 0.00156 AC: 65 AN: 41576

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.0209 AC: 108 AN: 5178

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00576 Hom.: 9

Bravo AF: 0.00485

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00563

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.39
CADD	Benign	8.1
DANN	Benign	0.69
PhyloP100		1.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2279582; hg19: chr5-127671232; COSMIC: COSV52527850;