6-168441442-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001166412.2(SMOC2):​c.72C>G​(p.Phe24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000597 in 1,508,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

SMOC2
NM_001166412.2 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.356
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05005476).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMOC2NM_001166412.2 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 ENST00000356284.7 NP_001159884.1 Q9H3U7-1
SMOC2NM_022138.3 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 NP_071421.1 Q9H3U7-2
SMOC2XM_011536065.2 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 XP_011534367.1
SMOC2XM_011536066.2 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 XP_011534368.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMOC2ENST00000356284.7 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 1 NM_001166412.2 ENSP00000348630.3 Q9H3U7-1
SMOC2ENST00000354536.9 linkc.72C>G p.Phe24Leu missense_variant Exon 1 of 13 1 ENSP00000346537.5 Q9H3U7-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000289
AC:
3
AN:
103632
Hom.:
0
AF XY:
0.0000174
AC XY:
1
AN XY:
57520
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000150
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000516
AC:
7
AN:
1355938
Hom.:
0
Cov.:
31
AF XY:
0.00000299
AC XY:
2
AN XY:
668408
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000189
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:
9.40e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.72C>G (p.F24L) alteration is located in exon 1 (coding exon 1) of the SMOC2 gene. This alteration results from a C to G substitution at nucleotide position 72, causing the phenylalanine (F) at amino acid position 24 to be replaced by a leucine (L). 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
0.52
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
14
DANN
Benign
0.96
DEOGEN2
Benign
0.018
T;.
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.050
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.55
N;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.36
N;N
REVEL
Benign
0.099
Sift
Benign
0.76
T;T
Sift4G
Benign
0.53
T;T
Polyphen
0.0010
B;B
Vest4
0.13
MutPred
0.28
Loss of methylation at K23 (P = 0.0289);Loss of methylation at K23 (P = 0.0289);
MVP
0.21
MPC
0.17
ClinPred
0.046
T
GERP RS
3.5
Varity_R
0.061
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1378774701; hg19: chr6-168842122; API