NM_001166412.2:c.178T>G

Variant names:

• chr6-168510008-T-G
• rs180941263
• NM_001166412.2:c.178T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001166412.2(SMOC2):​c.178T>G​(p.Phe60Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. F60L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMOC2 NM_001166412.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.94
• Publications: 0 publications found

Genes affected

SMOC2 (HGNC:20323): (SPARC related modular calcium binding 2) This gene encodes a member of the SPARC family (secreted protein acidic and rich in cysteine/osteonectin/BM-40), which are highly expressed during embryogenesis and wound healing. The gene product is a matricellular protein which promotes matrix assembly and can stimulate endothelial cell proliferation and migration, as well as angiogenic activity. Associated with pulmonary function, this secretory gene product contains a Kazal domain, two thymoglobulin type-1 domains, and two EF-hand calcium-binding domains. The encoded protein may serve as a target for controlling angiogenesis in tumor growth and myocardial ischemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

SMOC2 Gene-Disease associations (from GenCC):

• dentin dysplasia type I

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• atypical dentin dysplasia due to SMOC2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC2	NM_001166412.2	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13	ENST00000356284.7	NP_001159884.1
SMOC2	NM_022138.3	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13		NP_071421.1
SMOC2	XM_011536065.2	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13		XP_011534367.1
SMOC2	XM_011536066.2	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13		XP_011534368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMOC2	ENST00000356284.7	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13	1	NM_001166412.2	ENSP00000348630.3
SMOC2	ENST00000354536.9	c.178T>G	p.Phe60Val	missense_variant	Exon 2 of 13	1		ENSP00000346537.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		6.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.94	P;D
Vest4		0.90
MutPred		0.75		Gain of MoRF binding (P = 0.2322);Gain of MoRF binding (P = 0.2322);
MVP		0.51
MPC		0.70
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.73
gMVP		0.87
Mutation Taster		=40/60	disease causing

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: rs180941263; hg19: chr6-168910688;