11-9030003-C-A

Variant names:

• chr11-9030003-C-A
• rs778061686
• NM_001367977.2:c.2384G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001367977.2(SCUBE2):​c.2384G>T​(p.Arg795Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R795Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 1 publications found

Genes affected

SCUBE2 (HGNC:30425): (signal peptide, CUB domain and EGF like domain containing 2) Predicted to enable calcium ion binding activity; hedgehog family protein binding activity; and lipid binding activity. Predicted to be involved in signal transduction. Predicted to act upstream of or within several processes, including positive regulation of chondrocyte proliferation; positive regulation of osteoblast differentiation; and positive regulation of smoothened signaling pathway. Predicted to be located in extracellular region. Predicted to be active in cell surface and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

NRIP3-DT (HGNC:55524): (NRIP3 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367977.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE2	NM_001367977.2	MANE Select	c.2384G>T	p.Arg795Leu	missense	Exon 19 of 23	NP_001354906.1	A0A3B3ISZ7
	SCUBE2	NM_001330199.3		c.2297G>T	p.Arg766Leu	missense	Exon 18 of 22	NP_001317128.1	Q9NQ36-1
	SCUBE2	NM_020974.4		c.2213G>T	p.Arg738Leu	missense	Exon 18 of 22	NP_066025.2	Q9NQ36-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE2	ENST00000649792.2	MANE Select	c.2384G>T	p.Arg795Leu	missense	Exon 19 of 23	ENSP00000497523.1	A0A3B3ISZ7
	SCUBE2	ENST00000450649.6	TSL:1	c.1919G>T	p.Arg640Leu	missense	Exon 15 of 18	ENSP00000415187.2	Q9NQ36-3
	SCUBE2	ENST00000309263.7	TSL:5	c.2297G>T	p.Arg766Leu	missense	Exon 18 of 22	ENSP00000310658.3	Q9NQ36-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.65		Loss of disorder (P = 0.0389)
MVP		0.71
MPC		0.91
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.80
gMVP		0.48
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs778061686; hg19: chr11-9051550;