6-169223401-C-G

Variant names:

• chr6-169223401-C-G
• rs1020938067
• NM_003247.5:c.2848G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003247.5(THBS2):​c.2848G>C​(p.Glu950Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E950K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: THBS2 NM_003247.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37
• Publications: 0 publications found

Genes affected

THBS2 (HGNC:11786): (thrombospondin 2) The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration. [provided by RefSeq, Jul 2008]

THBS2-AS1 (HGNC:56059): (THBS2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003247.5. 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
	THBS2	NM_003247.5	MANE Select	c.2848G>C	p.Glu950Gln	missense	Exon 18 of 22	NP_003238.2
	THBS2	NM_001381939.1		c.2674G>C	p.Glu892Gln	missense	Exon 17 of 21	NP_001368868.1	A0A7I2V585
	THBS2	NM_001381942.1		c.2617G>C	p.Glu873Gln	missense	Exon 18 of 22	NP_001368871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THBS2	ENST00000617924.6	TSL:1 MANE Select	c.2848G>C	p.Glu950Gln	missense	Exon 18 of 22	ENSP00000482784.1	P35442
	THBS2	ENST00000366787.7	TSL:1	c.2848G>C	p.Glu950Gln	missense	Exon 19 of 23	ENSP00000355751.3	P35442
	THBS2	ENST00000649844.1		c.2863G>C	p.Glu955Gln	missense	Exon 18 of 22	ENSP00000497834.1	A0A3B3ITK0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.31		Loss of catalytic residue at E950 (P = 0.0331)
MVP		0.98
MPC		0.95
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.68
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1020938067; hg19: chr6-169623496;