5-128537409-C-A

Variant names:

• chr5-128537409-C-A
• rs750055830
• NM_001999.4:c.195G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001999.4(FBN2):​c.195G>T​(p.Glu65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E65E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12399626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.195G>T	p.Glu65Asp	missense_variant	Exon 1 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.195G>T	p.Glu65Asp	missense_variant	Exon 1 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.195G>T	p.Glu65Asp	missense_variant	Exon 1 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000931

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457792 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;.;T;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.71	T;.;.;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.88	L;.;L;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.40	N;.;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.43	T;.;T;T;T
Sift4G	Benign	0.51	.;.;.;T;T
Polyphen		0.0	B;.;B;B;B
Vest4		0.068
MutPred		0.20		Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);
MVP		0.45
MPC		0.21
ClinPred		0.065	T
GERP RS		0.80
Varity_R		0.082
gMVP		0.64

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: rs750055830; hg19: chr5-127873102;