6-168441383-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001166412.2(SMOC2):c.13C>T(p.Gln5Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,355,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: SMOC2 NM_001166412.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.854

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.99 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-168441383-C-T is Pathogenic according to our data. Variant chr6-168441383-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2871699.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMOC2	NM_001166412.2	c.13C>T	p.Gln5Ter	stop_gained	1/13	ENST00000356284.7
SMOC2	NM_022138.3	c.13C>T	p.Gln5Ter	stop_gained	1/13
SMOC2	XM_011536065.2	c.13C>T	p.Gln5Ter	stop_gained	1/13
SMOC2	XM_011536066.2	c.13C>T	p.Gln5Ter	stop_gained	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMOC2	ENST00000356284.7	c.13C>T	p.Gln5Ter	stop_gained	1/13	1	NM_001166412.2	P3
SMOC2	ENST00000354536.9	c.13C>T	p.Gln5Ter	stop_gained	1/13	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1355656 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 668610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.38e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 20, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SMOC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln5*) in the SMOC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMOC2 are known to be pathogenic (PMID: 22152679, 23317772). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.18	N
MutationTaster	Benign	1.0	A;A
Vest4		0.42
GERP RS		2.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-168842063;