11-9027451-G-A

Variant names:

• chr11-9027451-G-A
• rs141854880
• NM_001367977.2:c.2614C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367977.2(SCUBE2):​c.2614C>T​(p.Pro872Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P872H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2614C>T	p.Pro872Ser	missense	Exon 20 of 23	NP_001354906.1	A0A3B3ISZ7
	SCUBE2	NM_001330199.3		c.2527C>T	p.Pro843Ser	missense	Exon 19 of 22	NP_001317128.1	Q9NQ36-1
	SCUBE2	NM_020974.4		c.2443C>T	p.Pro815Ser	missense	Exon 19 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.2614C>T	p.Pro872Ser	missense	Exon 20 of 23	ENSP00000497523.1	A0A3B3ISZ7
	SCUBE2	ENST00000450649.6	TSL:1	c.2039-1597C>T		intron	N/A	ENSP00000415187.2	Q9NQ36-3
	SCUBE2	ENST00000309263.7	TSL:5	c.2527C>T	p.Pro843Ser	missense	Exon 19 of 22	ENSP00000310658.3	Q9NQ36-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.22
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.52
MutPred		0.65		Loss of glycosylation at P843 (P = 0.0207)
MVP		0.54
MPC		0.81
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.0010	Neutral
Varity_R		0.36
gMVP		0.37
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141854880; hg19: chr11-9048998;