rs62390671

Variant names:

• chr5-128537401-G-A
• rs62390671
• NM_001999.4:c.203C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-128537401-G-A
• chr5-128537401-G-C

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.203C>T​(p.Ala68Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,610,132 control chromosomes in the GnomAD database, including 1,512 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A68S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (89 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1423 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 2.11
• Publications: 9 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=0.0015599728).
• BP6: Variant 5-128537401-G-A is Benign according to our data. Variant chr5-128537401-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94020.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 = 0.0321 (4887/152310) while in subpopulation NFE AF = 0.0465 (3162/68014). AF 95% confidence interval is 0.0451. There are 89 homozygotes in GnomAd4. There are 2250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4887 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.203C>T	p.Ala68Val	missense	Exon 1 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.203C>T	p.Ala68Val	missense	Exon 1 of 65	ENSP00000262464.4	P35556-1
	FBN2	ENST00000502468.5	TSL:1	c.203C>T	p.Ala68Val	missense	Exon 1 of 8	ENSP00000424753.1	E9PHW4
	FBN2	ENST00000939405.1		c.203C>T	p.Ala68Val	missense	Exon 1 of 64	ENSP00000609464.1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4887 AN: 152192 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0304 AC: 7288 AN: 239974 AF XY: 0.0307

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0420 AC: 61242 AN: 1457822 Hom.: 1423 Cov.: 32 AF XY: 0.0415 AC XY: 30068 AN XY: 725194

African (AFR) AF: 0.0133 AC: 445 AN: 33464

American (AMR) AF: 0.0182 AC: 811 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 1519 AN: 26060

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0132 AC: 1134 AN: 85790

European-Finnish (FIN) AF: 0.0350 AC: 1775 AN: 50762

Middle Eastern (MID) AF: 0.0144 AC: 83 AN: 5762

European-Non Finnish (NFE) AF: 0.0479 AC: 53274 AN: 1111440

Other (OTH) AF: 0.0365 AC: 2200 AN: 60248

GnomAD4 genome AF: 0.0321 AC: 4887 AN: 152310 Hom.: 89 Cov.: 32 AF XY: 0.0302 AC XY: 2250 AN XY: 74482

African (AFR) AF: 0.0146 AC: 607 AN: 41592

American (AMR) AF: 0.0231 AC: 353 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4832

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3162 AN: 68014

Other (OTH) AF: 0.0340 AC: 72 AN: 2116

Alfa AF: 0.0428 Hom.: 369

Bravo AF: 0.0311

TwinsUK AF: 0.0488 AC: 181

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.0139 AC: 61

ESP6500EA AF: 0.0466 AC: 400

ExAC AF: 0.0300 AC: 3635

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Congenital contractural arachnodactyly (5)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)
-	-	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	0.085
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.23
ClinPred		0.0077	T
GERP RS		2.9
PromoterAI		0.046	Neutral
Varity_R		0.039
gMVP		0.58
Mutation Taster		=96/4	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: rs62390671; hg19: chr5-127873094;