chr5-128303067-A-G

Variant names:

• chr5-128303067-A-G
• rs11955288
• NM_001999.4:c.5823T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001999.4(FBN2):​c.5823T>C​(p.His1941His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 1,607,754 control chromosomes in the GnomAD database, including 8,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (769 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7666 hom.)
• Consequence: FBN2 NM_001999.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.30
• Publications: 13 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=-0.48).
• BP6: Variant 5-128303067-A-G is Benign according to our data. Variant chr5-128303067-A-G is described in ClinVar as Benign. ClinVar VariationId is 129044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0999 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.5823T>C	p.His1941His	synonymous	Exon 46 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.5823T>C	p.His1941His	synonymous	Exon 46 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.5724T>C	p.His1908His	synonymous	Exon 45 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.5670T>C	p.His1890His	synonymous	Exon 45 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14377 AN: 152054 Hom.: 768 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0885

GnomAD2 exomes AF: 0.0937 AC: 23553 AN: 251308 AF XY: 0.0944

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0918

Gnomad ASJ exome AF: 0.0831

Gnomad EAS exome AF: 0.0569

Gnomad FIN exome AF: 0.0730

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0922

GnomAD4 exome AF: 0.100 AC: 146194 AN: 1455582 Hom.: 7666 Cov.: 29 AF XY: 0.101 AC XY: 73124 AN XY: 724560

African (AFR) AF: 0.0978 AC: 3263 AN: 33348

American (AMR) AF: 0.0888 AC: 3971 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 2061 AN: 26086

East Asian (EAS) AF: 0.0614 AC: 2435 AN: 39640

South Asian (SAS) AF: 0.106 AC: 9119 AN: 86132

European-Finnish (FIN) AF: 0.0702 AC: 3748 AN: 53366

Middle Eastern (MID) AF: 0.122 AC: 700 AN: 5750

European-Non Finnish (NFE) AF: 0.104 AC: 114872 AN: 1106336

Other (OTH) AF: 0.100 AC: 6025 AN: 60214

GnomAD4 genome AF: 0.0945 AC: 14378 AN: 152172 Hom.: 769 Cov.: 32 AF XY: 0.0918 AC XY: 6827 AN XY: 74400

African (AFR) AF: 0.101 AC: 4189 AN: 41532

American (AMR) AF: 0.0795 AC: 1214 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0793 AC: 275 AN: 3468

East Asian (EAS) AF: 0.0594 AC: 307 AN: 5172

South Asian (SAS) AF: 0.108 AC: 518 AN: 4816

European-Finnish (FIN) AF: 0.0643 AC: 681 AN: 10584

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6919 AN: 68002

Other (OTH) AF: 0.0881 AC: 186 AN: 2112

Alfa AF: 0.0982 Hom.: 1075

Bravo AF: 0.0953

Asia WGS AF: 0.0740 AC: 261 AN: 3478

EpiCase AF: 0.0984

EpiControl AF: 0.0978

ClinVar

ClinVar submissions

Significance: 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	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.4
DANN	Benign	0.49
PhyloP100		1.3
Mutation Taster		=93/7	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: rs11955288; hg19: chr5-127638759; COSMIC: COSV52516937;