5-128290739-G-C

Variant names:

• chr5-128290739-G-C
• NM_001999.4:c.6438C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001999.4(FBN2):​c.6438C>G​(p.Asp2146Glu) 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 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036011815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.6438C>G	p.Asp2146Glu	missense_variant	Exon 50 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.6285C>G	p.Asp2095Glu	missense_variant	Exon 49 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.6438C>G	p.Asp2146Glu	missense_variant	Exon 50 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.3222C>G		non_coding_transcript_exon_variant	Exon 25 of 38
FBN2	ENST00000703785.1	n.3141C>G		non_coding_transcript_exon_variant	Exon 24 of 27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.015
DANN	Benign	0.24
DEOGEN2	Benign	0.24	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	T;.;.
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.3	N;.;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.71	N;.;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.13
MutPred		0.51		Gain of disorder (P = 0.1724);.;Gain of disorder (P = 0.1724);
MVP		0.22
MPC		0.22
ClinPred		0.043	T
GERP RS		-0.31
Varity_R		0.036
gMVP		0.18

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: chr5-127626431;