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: 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 -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.

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.6511+15A>G		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.6511+15A>G		intron	N/A	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.6412+15A>G		intron	N/A	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.6358+15A>G		intron	N/A	ENSP00000609463.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;