rs28763953

Variant names:

• chr5-128395085-G-C
• rs28763953
• NM_001999.4:c.1231+37C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.1231+37C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 1,611,942 control chromosomes in the GnomAD database, including 1,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (94 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1570 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.25
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-128395085-G-C is Benign according to our data. Variant chr5-128395085-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 258507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0305 (4641/152284) while in subpopulation NFE AF = 0.0439 (2984/68010). AF 95% confidence interval is 0.0426. There are 94 homozygotes in GnomAd4. There are 2152 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4641 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.1231+37C>G		intron	N/A	NP_001990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN2	ENST00000262464.9	TSL:1 MANE Select	c.1231+37C>G		intron	N/A	ENSP00000262464.4
	FBN2	ENST00000939405.1		c.1132+37C>G		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.1079-1717C>G		intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4640 AN: 152166 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.00878

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0390

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0350 AC: 8772 AN: 250556 AF XY: 0.0341

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0439 AC: 64059 AN: 1459658 Hom.: 1570 Cov.: 31 AF XY: 0.0431 AC XY: 31300 AN XY: 726244

African (AFR) AF: 0.00694 AC: 232 AN: 33440

American (AMR) AF: 0.0454 AC: 2029 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0644 AC: 1682 AN: 26122

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39640

South Asian (SAS) AF: 0.0232 AC: 1998 AN: 86218

European-Finnish (FIN) AF: 0.0331 AC: 1769 AN: 53378

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5754

European-Non Finnish (NFE) AF: 0.0484 AC: 53760 AN: 1110106

Other (OTH) AF: 0.0415 AC: 2501 AN: 60288

GnomAD4 genome AF: 0.0305 AC: 4641 AN: 152284 Hom.: 94 Cov.: 32 AF XY: 0.0289 AC XY: 2152 AN XY: 74470

African (AFR) AF: 0.00876 AC: 364 AN: 41562

American (AMR) AF: 0.0391 AC: 598 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4826

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0439 AC: 2984 AN: 68010

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

Alfa AF: 0.0407 Hom.: 21

Bravo AF: 0.0306

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.078
DANN	Benign	0.65
PhyloP100		-2.3
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: rs28763953; hg19: chr5-127730778; COSMIC: COSV107280890;