5-128286736-C-G

Variant names:

• chr5-128286736-C-G
• NM_001999.4:c.6994G>C

Variant summary

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

The NM_001999.4(FBN2):​c.6994G>C​(p.Asp2332His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2332N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6994G>C	p.Asp2332His	missense_variant	Exon 55 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6841G>C	p.Asp2281His	missense_variant	Exon 54 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6994G>C	p.Asp2332His	missense_variant	Exon 55 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3778G>C		non_coding_transcript_exon_variant	Exon 30 of 38

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727202

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Uncertain	0.73	D;.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.8	L;.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.027	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.27
MutPred		0.72		Gain of catalytic residue at R2330 (P = 0.1305);.;Gain of catalytic residue at R2330 (P = 0.1305);
MVP		0.87
MPC		0.48
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127622428;