6-168441432-C-A

Variant names:

• chr6-168441432-C-A
• rs1238385224
• NM_001166412.2:c.62C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001166412.2(SMOC2):​c.62C>A​(p.Ala21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,358,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A21A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SMOC2 NM_001166412.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.138
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14390525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMOC2	NM_001166412.2	c.62C>A	p.Ala21Asp	missense_variant	Exon 1 of 13	ENST00000356284.7	NP_001159884.1
SMOC2	NM_022138.3	c.62C>A	p.Ala21Asp	missense_variant	Exon 1 of 13		NP_071421.1
SMOC2	XM_011536065.2	c.62C>A	p.Ala21Asp	missense_variant	Exon 1 of 13		XP_011534367.1
SMOC2	XM_011536066.2	c.62C>A	p.Ala21Asp	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	c.62C>A	p.Ala21Asp	missense_variant	Exon 1 of 13	1	NM_001166412.2	ENSP00000348630.3
SMOC2	ENST00000354536.9	c.62C>A	p.Ala21Asp	missense_variant	Exon 1 of 13	1		ENSP00000346537.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1358064 Hom.: 0 Cov.: 32 AF XY: 0.00000299 AC XY: 2 AN XY: 669470

African (AFR) AF: 0.00 AC: 0 AN: 27454

American (AMR) AF: 0.00 AC: 0 AN: 32202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24112

East Asian (EAS) AF: 0.00 AC: 0 AN: 30760

South Asian (SAS) AF: 0.00 AC: 0 AN: 75822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4146

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1065074

Other (OTH) AF: 0.00 AC: 0 AN: 56406

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62C>A (p.A21D) alteration is located in exon 1 (coding exon 1) of the SMOC2 gene. This alteration results from a C to A substitution at nucleotide position 62, causing the alanine (A) at amino acid position 21 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.14
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.21
Sift	Benign	0.068	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.18	B;B
Vest4		0.40
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0027);Gain of relative solvent accessibility (P = 0.0027);
MVP		0.55
MPC		0.36
ClinPred		0.34	T
GERP RS		4.4
PromoterAI		0.12	Neutral
Varity_R		0.25
gMVP		0.58
Mutation Taster		=61/39	polymorphism

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: rs1238385224; hg19: chr6-168842112;