Genetic Variant SMOC2:p.Ala13Thr (chr6-168441407-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001166412.2(SMOC2):c.37G>A(p.Ala13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,356,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A13P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

SMOC2
NM_001166412.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.154

Publications

0 publications found

Variant links:

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

SMOC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.069830924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC2	NM_001166412.2 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13	ENST00000356284.7	NP_001159884.1	Q9H3U7-1
SMOC2	NM_022138.3 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13		NP_071421.1	Q9H3U7-2
SMOC2	XM_011536065.2 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13		XP_011534367.1
SMOC2	XM_011536066.2 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13		XP_011534368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMOC2	ENST00000356284.7 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13	1	NM_001166412.2	ENSP00000348630.3		Q9H3U7-1
SMOC2	ENST00000354536.9 link	c.37G>A	p.Ala13Thr	missense_variant	Exon 1 of 13	1		ENSP00000346537.5		Q9H3U7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1356818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27450

American (AMR)

AF:

0.00

AC:

AN:

32404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24170

East Asian (EAS)

AF:

0.00

AC:

AN:

30814

South Asian (SAS)

AF:

0.00

AC:

AN:

75920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

9.38e-7

AC:

AN:

1065554

Other (OTH)

AF:

0.00

AC:

AN:

56456

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.027

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.070

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

N;N

PhyloP100

0.15

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.019

Sift

Benign

0.36

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0

B;B

Vest4

0.14

MutPred

0.39

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.18

MPC

0.14

ClinPred

0.054

GERP RS

1.2

PromoterAI

-0.053

Neutral

(source)

Varity_R

0.085

gMVP

0.46

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over