rs56131649

Variant names:

• chr5-128289867-T-C
• rs56131649
• NM_001999.4:c.6511+15A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128289867-T-C
• chr5-128289867-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001999.4(FBN2):​c.6511+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,475,690 control chromosomes in the GnomAD database, including 20,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1909 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18392 hom.)
• Consequence: FBN2 NM_001999.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.37
• Publications: 6 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=-0.81).
• BP6: Variant 5-128289867-T-C is Benign according to our data. Variant chr5-128289867-T-C is described in ClinVar as Benign. ClinVar VariationId is 137345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6511+15A>G		intron_variant	Intron 51 of 64	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6358+15A>G		intron_variant	Intron 50 of 63		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6511+15A>G		intron_variant	Intron 51 of 64	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3295+15A>G		intron_variant	Intron 26 of 37
FBN2	ENST00000703785.1	n.3214+15A>G		intron_variant	Intron 25 of 26

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21759 AN: 151968 Hom.: 1901 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.179 AC: 44026 AN: 246426 AF XY: 0.176

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.156

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.160 AC: 212230 AN: 1323604 Hom.: 18392 Cov.: 20 AF XY: 0.161 AC XY: 107242 AN XY: 666080

African (AFR) AF: 0.0483 AC: 1493 AN: 30884

American (AMR) AF: 0.288 AC: 12770 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3009 AN: 25266

East Asian (EAS) AF: 0.180 AC: 6969 AN: 38810

South Asian (SAS) AF: 0.177 AC: 14642 AN: 82776

European-Finnish (FIN) AF: 0.221 AC: 11748 AN: 53170

Middle Eastern (MID) AF: 0.0779 AC: 427 AN: 5484

European-Non Finnish (NFE) AF: 0.155 AC: 152904 AN: 987276

Other (OTH) AF: 0.149 AC: 8268 AN: 55610

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152086 Hom.: 1909 Cov.: 32 AF XY: 0.148 AC XY: 10968 AN XY: 74332

African (AFR) AF: 0.0531 AC: 2206 AN: 41512

American (AMR) AF: 0.227 AC: 3469 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 405 AN: 3470

East Asian (EAS) AF: 0.167 AC: 863 AN: 5172

South Asian (SAS) AF: 0.184 AC: 889 AN: 4820

European-Finnish (FIN) AF: 0.222 AC: 2344 AN: 10546

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11151 AN: 67988

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.147 Hom.: 543

Bravo AF: 0.137

Asia WGS AF: 0.228 AC: 791 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 31, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

6511+15A>G in intron 51 of FBN2: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 16.1% (1383/8594) of European American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs56131649). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital contractural arachnodactyly Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Mar 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FBN2 c.6511+15A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 20207/102662 control chromosomes (2001 homozygotes) at a frequency of 0.1968, which is approximately 157463 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. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.020
DANN	Benign	0.44
PhyloP100		-2.4
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: rs56131649; hg19: chr5-127625559; COSMIC: COSV52511082;