rs112428886

Variant names:

• chr5-128408712-C-T
• rs112428886
• NM_001999.4:c.1040G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-128408712-C-T
• chr5-128408712-C-A
• chr5-128408712-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001999.4(FBN2):​c.1040G>A​(p.Arg347His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 1,613,982 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (34 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.81
• Publications: 10 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 (MetaRNN=0.017316043).
• BP6: Variant 5-128408712-C-T is Benign according to our data. Variant chr5-128408712-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210993.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 = 0.00412 (628/152248) while in subpopulation NFE AF = 0.00607 (413/68020). AF 95% confidence interval is 0.00559. There are 2 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 628 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.1040G>A	p.Arg347His	missense	Exon 8 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.1040G>A	p.Arg347His	missense	Exon 8 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000939405.1		c.941G>A	p.Arg314His	missense	Exon 7 of 64	ENSP00000609464.1
	FBN2	ENST00000939404.1		c.1040G>A	p.Arg347His	missense	Exon 8 of 64	ENSP00000609463.1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 628 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00429 AC: 1077 AN: 250988 AF XY: 0.00441

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.00649

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00608 AC: 8890 AN: 1461734 Hom.: 34 Cov.: 32 AF XY: 0.00606 AC XY: 4406 AN XY: 727172

African (AFR) AF: 0.00114 AC: 38 AN: 33476

American (AMR) AF: 0.00226 AC: 101 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86254

European-Finnish (FIN) AF: 0.00680 AC: 363 AN: 53418

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.00710 AC: 7897 AN: 1111908

Other (OTH) AF: 0.00450 AC: 272 AN: 60388

GnomAD4 genome AF: 0.00412 AC: 628 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74442

African (AFR) AF: 0.00135 AC: 56 AN: 41548

American (AMR) AF: 0.00458 AC: 70 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00607 AC: 413 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00559 Hom.: 10

Bravo AF: 0.00385

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00539

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	2	Congenital contractural arachnodactyly (2)
-	-	2	Connective tissue disorder (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.94	L
PhyloP100		2.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.69
Sift	Benign	0.075	T
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.75
MVP		0.90
MPC		0.84
ClinPred		0.010	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.42
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112428886; hg19: chr5-127744405; COSMIC: COSV52512755;