rs748419325

chr5-128376806-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_001999.4(FBN2):c.1897A>G(p.Ile633Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,326 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP6: Variant 5-128376806-T-C is Benign according to our data. Variant chr5-128376806-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547353.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.1897A>G	p.Ile633Val	missense_variant	14/65	ENST00000262464.9
FBN2	XM_017009228.3	c.1744A>G	p.Ile582Val	missense_variant	13/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.1897A>G	p.Ile633Val	missense_variant	14/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.1798A>G	p.Ile600Val	missense_variant	13/33	2
FBN2	ENST00000511489.1	n.118A>G		non_coding_transcript_exon_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251072 Hom.: 1 AF XY: 0.00 AC XY: 0 AN XY: 135684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461326 Hom.: 1 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Congenital contractural arachnodactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;.;.;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.17	N;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.67	N;.;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.36	T;.;T;T
Polyphen		0.90	P;.;P;P
Vest4		0.59
MutPred		0.51		Gain of catalytic residue at I633 (P = 0.0767);.;Gain of catalytic residue at I633 (P = 0.0767);.;
MVP		0.79
MPC		0.26
ClinPred		0.59	D
GERP RS		4.6
Varity_R		0.11
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs748419325; hg19: chr5-127712499;