NM_001367977.2:c.2881A>G

Variant names:

• chr11-9021929-T-C
• rs1334161250
• NM_001367977.2:c.2881A>G

Variant summary

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

The NM_001367977.2(SCUBE2):​c.2881A>G​(p.Ile961Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28
• 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: 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.2881A>G	p.Ile961Val	missense	Exon 22 of 23	NP_001354906.1	A0A3B3ISZ7
	SCUBE2	NM_001330199.3		c.2794A>G	p.Ile932Val	missense	Exon 21 of 22	NP_001317128.1	Q9NQ36-1
	SCUBE2	NM_020974.4		c.2710A>G	p.Ile904Val	missense	Exon 21 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.2881A>G	p.Ile961Val	missense	Exon 22 of 23	ENSP00000497523.1	A0A3B3ISZ7
	SCUBE2	ENST00000450649.6	TSL:1	c.2218A>G	p.Ile740Val	missense	Exon 17 of 18	ENSP00000415187.2	Q9NQ36-3
	SCUBE2	ENST00000309263.7	TSL:5	c.2794A>G	p.Ile932Val	missense	Exon 21 of 22	ENSP00000310658.3	Q9NQ36-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251412 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461506 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

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	0.60
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.81	L
PhyloP100		6.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.91	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.35		Gain of disorder (P = 0.3198)
MVP		0.94
MPC		0.29
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.51
Mutation Taster		=81/19	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: rs1334161250; hg19: chr11-9043476;