5-128537493-C-T

Variant names:

• chr5-128537493-C-T
• rs55715053
• NM_001999.4:c.111G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.111G>A​(p.Pro37Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0919 in 1,584,512 control chromosomes in the GnomAD database, including 8,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P37P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2096 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6394 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.972
• Publications: 8 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-128537493-C-T is Benign according to our data. Variant chr5-128537493-C-T is described in ClinVar as Benign. ClinVar VariationId is 129034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.972 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 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.111G>A	p.Pro37Pro	synonymous	Exon 1 of 65	NP_001990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.111G>A	p.Pro37Pro	synonymous	Exon 1 of 65	ENSP00000262464.4
	FBN2	ENST00000502468.5	TSL:1	c.111G>A	p.Pro37Pro	synonymous	Exon 1 of 8	ENSP00000424753.1
	FBN2	ENST00000939405.1		c.111G>A	p.Pro37Pro	synonymous	Exon 1 of 64	ENSP00000609464.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20807 AN: 152076 Hom.: 2080 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0782

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0855

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0882 AC: 17101 AN: 193804 AF XY: 0.0864

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.0751

Gnomad EAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0875

Gnomad NFE exome AF: 0.0878

Gnomad OTH exome AF: 0.0865

GnomAD4 exome AF: 0.0871 AC: 124726 AN: 1432318 Hom.: 6394 Cov.: 32 AF XY: 0.0865 AC XY: 61464 AN XY: 710332

African (AFR) AF: 0.289 AC: 9551 AN: 33004

American (AMR) AF: 0.0614 AC: 2522 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.0733 AC: 1876 AN: 25596

East Asian (EAS) AF: 0.0114 AC: 436 AN: 38296

South Asian (SAS) AF: 0.0852 AC: 7066 AN: 82948

European-Finnish (FIN) AF: 0.0774 AC: 3575 AN: 46196

Middle Eastern (MID) AF: 0.0837 AC: 478 AN: 5710

European-Non Finnish (NFE) AF: 0.0854 AC: 93978 AN: 1100180

Other (OTH) AF: 0.0884 AC: 5244 AN: 59320

GnomAD4 genome AF: 0.137 AC: 20858 AN: 152194 Hom.: 2096 Cov.: 32 AF XY: 0.134 AC XY: 9985 AN XY: 74422

African (AFR) AF: 0.287 AC: 11912 AN: 41520

American (AMR) AF: 0.0780 AC: 1194 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5168

South Asian (SAS) AF: 0.0779 AC: 376 AN: 4828

European-Finnish (FIN) AF: 0.0869 AC: 922 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0854 AC: 5809 AN: 67984

Other (OTH) AF: 0.107 AC: 227 AN: 2112

Alfa AF: 0.0931 Hom.: 274

Bravo AF: 0.141

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.46
CADD	Benign	8.0
DANN	Benign	0.96
PhyloP100		-0.97
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	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: rs55715053; hg19: chr5-127873186; COSMIC: COSV52505361; COSMIC: COSV52505361;