rs34201226

Variant names:

• chr5-128332928-G-A
• rs34201226
• NM_001999.4:c.4206C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128332928-G-A
• chr5-128332928-G-C
• chr5-128332928-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001999.4(FBN2):​c.4206C>T​(p.Asn1402Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,613,896 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.785
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-128332928-G-A is Benign according to our data. Variant chr5-128332928-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.785 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00284 (433/152282) while in subpopulation AFR AF = 0.00951 (395/41556). AF 95% confidence interval is 0.00873. There are 4 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 433 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.4206C>T	p.Asn1402Asn	synonymous	Exon 32 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.4206C>T	p.Asn1402Asn	synonymous	Exon 32 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.4107C>T	p.Asn1369Asn	synonymous	Exon 31 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.4053C>T	p.Asn1351Asn	synonymous	Exon 31 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251378 AF XY: 0.000891

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000392 AC: 573 AN: 1461614 Hom.: 4 Cov.: 31 AF XY: 0.000316 AC XY: 230 AN XY: 727124

African (AFR) AF: 0.00867 AC: 290 AN: 33454

American (AMR) AF: 0.00436 AC: 195 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111818

Other (OTH) AF: 0.000961 AC: 58 AN: 60382

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74466

African (AFR) AF: 0.00951 AC: 395 AN: 41556

American (AMR) AF: 0.00177 AC: 27 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

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

Alfa AF: 0.000896 Hom.: 0

Bravo AF: 0.00333

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	not provided (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	-0.50
CADD	Benign	7.4
DANN	Benign	0.65
PhyloP100		0.79
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34201226; hg19: chr5-127668620; COSMIC: COSV52519785;