rs146849637

Variant names:

• chr5-128446604-C-T
• rs146849637
• NM_001999.4:c.829G>A

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.829G>A​(p.Val277Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00335 in 1,613,522 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. V277A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: FBN2 NM_001999.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 6.07
• 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 (MetaRNN=0.023231387).
• BP6: Variant 5-128446604-C-T is Benign according to our data. Variant chr5-128446604-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213259.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 = 0.00202 (307/152316) while in subpopulation NFE AF = 0.00356 (242/68016). AF 95% confidence interval is 0.00319. There are 0 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 307 AD,Unknown 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.829G>A	p.Val277Ile	missense splice_region	Exon 7 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.829G>A	p.Val277Ile	missense splice_region	Exon 7 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000502468.5	TSL:1	c.829G>A	p.Val277Ile	missense splice_region	Exon 7 of 8	ENSP00000424753.1	E9PHW4
	FBN2	ENST00000939405.1		c.730G>A	p.Val244Ile	missense splice_region	Exon 6 of 64	ENSP00000609464.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00168 AC: 423 AN: 251430 AF XY: 0.00166

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00349 AC: 5095 AN: 1461206 Hom.: 17 Cov.: 30 AF XY: 0.00336 AC XY: 2440 AN XY: 726918

African (AFR) AF: 0.00114 AC: 38 AN: 33470

American (AMR) AF: 0.000358 AC: 16 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00141 AC: 75 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00430 AC: 4784 AN: 1111582

Other (OTH) AF: 0.00297 AC: 179 AN: 60356

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74486

African (AFR) AF: 0.000625 AC: 26 AN: 41574

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00190

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00181 AC: 220

EpiCase AF: 0.00294

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Congenital contractural arachnodactyly (4)
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FBN2-related disorder (1)
-	1	-	Loeys-Dietz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	-0.77	N
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.43
Sift	Benign	0.68	T
Sift4G	Benign	0.73	T
Polyphen		0.99	D
Vest4		0.27
MVP		0.72
MPC		0.28
ClinPred		0.040	T
GERP RS		4.8
Varity_R		0.071
gMVP		0.14
Mutation Taster		=85/15	polymorphism

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: rs146849637; hg19: chr5-127782297;