11-9029916-A-G

Position:

• chr11-9029916-A-G

Variant summary

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

The NM_001367977.2(SCUBE2):​c.2471T>C​(p.Phe824Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

SCUBE2 (HGNC:):

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/exons	MANE	Protein	UniProt
SCUBE2	NM_001367977.2	c.2471T>C	p.Phe824Ser	missense_variant	19/23	ENST00000649792.2	NP_001354906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCUBE2	ENST00000649792.2	c.2471T>C	p.Phe824Ser	missense_variant	19/23		NM_001367977.2	ENSP00000497523.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2024

The c.2300T>C (p.F767S) alteration is located in exon 18 (coding exon 18) of the SCUBE2 gene. This alteration results from a T to C substitution at nucleotide position 2300, causing the phenylalanine (F) at amino acid position 767 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.7	.;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	.;D;T;D
Sift4G	Uncertain	0.0020	.;D;D;D
Polyphen		1.0, 0.99, 0.99	.;D;D;D
Vest4		0.64, 0.73, 0.67
MutPred		0.50		.;Gain of disorder (P = 0.0349);.;.;
MVP		0.58
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.48
gMVP		0.52

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: chr11-9051463;