rs11955288

Positions:

• chr5-128303067-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 129044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-128303067-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.5823T>C	p.His1941His	synonymous_variant	46/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.5670T>C	p.His1890His	synonymous_variant	45/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.5823T>C	p.His1941His	synonymous_variant	46/65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2607T>C		non_coding_transcript_exon_variant	21/38
FBN2	ENST00000703785.1	n.2526T>C		non_coding_transcript_exon_variant	20/27

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

GnomAD3 exomes AF: 0.0937 AC: 23553 AN: 251308 Hom.: 1136 AF XY: 0.0944 AC XY: 12823 AN XY: 135830

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 SAS exome AF: 0.106

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

Gnomad4 AFR exome AF: 0.0978

Gnomad4 AMR exome AF: 0.0888

Gnomad4 ASJ exome AF: 0.0790

Gnomad4 EAS exome AF: 0.0614

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.100

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0795

Gnomad4 ASJ AF: 0.0793

Gnomad4 EAS AF: 0.0594

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0643

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0881

Alfa AF: 0.0984 Hom.: 843

Bravo AF: 0.0953

Asia WGS AF: 0.0740 AC: 261 AN: 3478

EpiCase AF: 0.0984

EpiControl AF: 0.0978

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	His1941His in exon 46 of FBN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.6% (466/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs11955288). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2017	Variant summary: The FBN2 c.5823T>C (p.His1941His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0948795 (11503/121238 control chromosomes [584 homozygotes]), which is approximately 75904 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.4
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs11955288; hg19: chr5-127638759; COSMIC: COSV52516937;