rs28763949

Variant names:

• chr5-128357402-T-C
• rs28763949
• NM_001999.4:c.2555-7A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128357402-T-C
• chr5-128357402-T-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.2555-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,716 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (5 hom.)
• Consequence: FBN2 NM_001999.4 splice_region, intron
• Scores: Splicing: ADA: 0.003255
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.72
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-128357402-T-C is Benign according to our data. Variant chr5-128357402-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137321.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 = 0.0014 (213/152292) while in subpopulation NFE AF = 0.00269 (183/68030). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 213 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.2555-7A>G		splice_region intron	N/A	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.2555-7A>G		splice_region intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.2456-7A>G		splice_region intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.2402-7A>G		splice_region intron	N/A	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251216 AF XY: 0.00132

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00265 AC: 3871 AN: 1461424 Hom.: 5 Cov.: 31 AF XY: 0.00256 AC XY: 1863 AN XY: 727020

African (AFR) AF: 0.000538 AC: 18 AN: 33458

American (AMR) AF: 0.000738 AC: 33 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00326 AC: 3624 AN: 1111648

Other (OTH) AF: 0.00238 AC: 144 AN: 60378

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74460

African (AFR) AF: 0.000361 AC: 15 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68030

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

Alfa AF: 0.00217 Hom.: 1

Bravo AF: 0.00136

EpiCase AF: 0.00284

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Congenital contractural arachnodactyly (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Congenital contractural arachnodactyly;C4015286:Macular degeneration, early-onset (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.030		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: rs28763949; hg19: chr5-127693094;