chr11-9025798-C-T

Variant names:

• chr11-9025798-C-T
• rs138426692
• NM_001367977.2:c.2758G>A

Variant summary

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

The NM_001367977.2(SCUBE2):​c.2758G>A​(p.Ala920Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 4 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 0 ACMG points.

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.2758G>A	p.Ala920Thr	missense	Exon 21 of 23	NP_001354906.1	A0A3B3ISZ7
	SCUBE2	NM_001330199.3		c.2671G>A	p.Ala891Thr	missense	Exon 20 of 22	NP_001317128.1	Q9NQ36-1
	SCUBE2	NM_020974.4		c.2587G>A	p.Ala863Thr	missense	Exon 20 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.2758G>A	p.Ala920Thr	missense	Exon 21 of 23	ENSP00000497523.1	A0A3B3ISZ7
	SCUBE2	ENST00000450649.6	TSL:1	c.2095G>A	p.Ala699Thr	missense	Exon 16 of 18	ENSP00000415187.2	Q9NQ36-3
	SCUBE2	ENST00000309263.7	TSL:5	c.2671G>A	p.Ala891Thr	missense	Exon 20 of 22	ENSP00000310658.3	Q9NQ36-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251428 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461886 Hom.: 1 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74426

African (AFR) AF: 0.0000241 AC: 1 AN: 41524

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.98	L
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.71		Gain of phosphorylation at A891 (P = 0.0385)
MVP		0.58
MPC		0.79
ClinPred		0.70	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.54
Mutation Taster		=54/46	polymorphism

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: rs138426692; hg19: chr11-9047345; COSMIC: COSV58542196; COSMIC: COSV58542196;