rs1060503504

Variant names:

• chr5-128305568-T-C
• NM_001999.4:c.5617A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-128305568-T-C
• chr5-128305568-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001999.4(FBN2):​c.5617A>G​(p.Ser1873Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.61

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a glycosylation_site O-linked (Glc) serine (size 0) in uniprot entity FBN2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.5617A>G	p.Ser1873Gly	missense_variant	Exon 44 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.5464A>G	p.Ser1822Gly	missense_variant	Exon 43 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.5617A>G	p.Ser1873Gly	missense_variant	Exon 44 of 65	1	NM_001999.4	ENSP00000262464.4
FBN2	ENST00000703783.1	n.2401A>G		non_coding_transcript_exon_variant	Exon 19 of 38
FBN2	ENST00000703785.1	n.2320A>G		non_coding_transcript_exon_variant	Exon 18 of 27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Pathogenic	0.72
Sift	Benign	0.060	T;.;T
Polyphen		0.82	P;.;P
Vest4		0.72
MutPred		0.89		Gain of catalytic residue at S1873 (P = 0.0575);.;Gain of catalytic residue at S1873 (P = 0.0575);
MVP		0.73
MPC		0.79
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.75

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: chr5-127641260;