NM_173050.5:c.2255C>T

Variant names:

• chr22-43211050-G-A
• rs751882996
• NM_173050.5:c.2255C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173050.5(SCUBE1):​c.2255C>T​(p.Thr752Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. T752S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCUBE1 NM_173050.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 0 publications found

Genes affected

SCUBE1 (HGNC:13441): (signal peptide, CUB domain and EGF like domain containing 1) This gene encodes a cell surface glycoprotein that is a member of the SCUBE (signal peptide, CUB domain, EGF (epidermal growth factor)-like protein) family. Family members have an amino-terminal signal peptide, nine copies of EGF-like repeats and a CUB domain at the carboxyl terminus. This protein is expressed in platelets and endothelial cells and may play an important role in vascular biology. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38311964).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173050.5. 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
	SCUBE1	NM_173050.5	MANE Select	c.2255C>T	p.Thr752Ile	missense	Exon 18 of 22	NP_766638.2	Q8IWY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE1	ENST00000360835.9	TSL:1 MANE Select	c.2255C>T	p.Thr752Ile	missense	Exon 18 of 22	ENSP00000354080.3	Q8IWY4
	SCUBE1	ENST00000911327.1		c.2192C>T	p.Thr731Ile	missense	Exon 18 of 22	ENSP00000581386.1
	SCUBE1	ENST00000911329.1		c.2192C>T	p.Thr731Ile	missense	Exon 18 of 22	ENSP00000581388.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461418 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.061
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.93	P
Vest4		0.34
MutPred		0.60		Loss of disorder (P = 0.0384)
MVP		0.30
MPC		1.4
ClinPred		0.99	D
GERP RS		0.43
Varity_R		0.18
gMVP		0.15
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751882996; hg19: chr22-43607056;