11-9025737-G-A

Variant names:

• chr11-9025737-G-A
• rs145135387
• NM_001367977.2:c.2819C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001367977.2(SCUBE2):​c.2819C>T​(p.Ala940Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (1 hom.)
• Consequence: SCUBE2 NM_001367977.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• Publications: 1 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22215185).

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.2819C>T	p.Ala940Val	missense	Exon 21 of 23	NP_001354906.1	A0A3B3ISZ7
	SCUBE2	NM_001330199.3		c.2732C>T	p.Ala911Val	missense	Exon 20 of 22	NP_001317128.1	Q9NQ36-1
	SCUBE2	NM_020974.4		c.2648C>T	p.Ala883Val	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.2819C>T	p.Ala940Val	missense	Exon 21 of 23	ENSP00000497523.1	A0A3B3ISZ7
	SCUBE2	ENST00000450649.6	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 16 of 18	ENSP00000415187.2	Q9NQ36-3
	SCUBE2	ENST00000309263.7	TSL:5	c.2732C>T	p.Ala911Val	missense	Exon 20 of 22	ENSP00000310658.3	Q9NQ36-1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000115 AC: 29 AN: 251466 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000615

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: 0.0000527 AC: 77 AN: 1461878 Hom.: 1 Cov.: 30 AF XY: 0.0000798 AC XY: 58 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.000788 AC: 68 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74442

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

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

Alfa AF: 0.0000138 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.29
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.52
MVP		0.78
MPC		0.81
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.57
Mutation Taster		=67/33	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: rs145135387; hg19: chr11-9047284;