rs875989843

Positions:

• chr6-168598828-T-A
• chr6-168598828-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001166412.2(SMOC2):​c.648T>A​(p.Cys216*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMOC2 NM_001166412.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.558

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-168598828-T-A is Pathogenic according to our data. Variant chr6-168598828-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 225685.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMOC2	NM_001166412.2	c.648T>A	p.Cys216*	stop_gained	8/13	ENST00000356284.7	NP_001159884.1
SMOC2	NM_022138.3	c.681T>A	p.Cys227*	stop_gained	8/13		NP_071421.1
SMOC2	XM_011536065.2	c.681T>A	p.Cys227*	stop_gained	8/13		XP_011534367.1
SMOC2	XM_011536066.2	c.648T>A	p.Cys216*	stop_gained	8/13		XP_011534368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMOC2	ENST00000356284.7	c.648T>A	p.Cys216*	stop_gained	8/13	1	NM_001166412.2	ENSP00000348630.3
SMOC2	ENST00000354536.9	c.681T>A	p.Cys227*	stop_gained	8/13	1		ENSP00000346537.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

DENTIN DYSPLASIA, TYPE I, WITH EXTREME MICRODONTIA AND MISSHAPEN TEETH Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 13, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.89
GERP RS		0.011

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989843; hg19: chr6-168999508;