rs1555238867

Variant names:

• chr11-9033742-C-T
• rs1555238867
• NM_001367977.2:c.2057G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001367977.2(SCUBE2):​c.2057G>A​(p.Cys686Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.75
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 11-9033742-C-T is Pathogenic according to our data. Variant chr11-9033742-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545106.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE2	NM_001367977.2	MANE Select	c.2057G>A	p.Cys686Tyr	missense	Exon 17 of 23	NP_001354906.1
	SCUBE2	NM_001330199.3		c.1970G>A	p.Cys657Tyr	missense	Exon 16 of 22	NP_001317128.1
	SCUBE2	NM_001170690.3		c.1592G>A	p.Cys531Tyr	missense	Exon 13 of 18	NP_001164161.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE2	ENST00000649792.2	MANE Select	c.2057G>A	p.Cys686Tyr	missense	Exon 17 of 23	ENSP00000497523.1
	SCUBE2	ENST00000450649.6	TSL:1	c.1592G>A	p.Cys531Tyr	missense	Exon 13 of 18	ENSP00000415187.2
	SCUBE2	ENST00000309263.7	TSL:5	c.1970G>A	p.Cys657Tyr	missense	Exon 16 of 22	ENSP00000310658.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral arteriovenous malformation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.7
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		1.0
MutPred		0.94		Loss of disorder (P = 0.065)
MVP		0.96
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.95
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555238867; hg19: chr11-9055289;