10-72063048-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001244950.2(SPOCK2):​c.1106G>A​(p.Arg369His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,553,668 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SPOCK2
NM_001244950.2 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83
Variant links:
Genes affected
SPOCK2 (HGNC:13564): (SPARC (osteonectin), cwcv and kazal like domains proteoglycan 2) This gene encodes a protein which binds with glycosaminoglycans to form part of the extracellular matrix. The protein contains thyroglobulin type-1, follistatin-like, and calcium-binding domains, and has glycosaminoglycan attachment sites in the acidic C-terminal region. Three alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPOCK2NM_001244950.2 linkc.1106G>A p.Arg369His missense_variant Exon 10 of 11 ENST00000373109.7 NP_001231879.1 Q92563-1
SPOCK2NM_014767.2 linkc.1106G>A p.Arg369His missense_variant Exon 11 of 12 NP_055582.1 Q92563-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPOCK2ENST00000373109.7 linkc.1106G>A p.Arg369His missense_variant Exon 10 of 11 1 NM_001244950.2 ENSP00000362201.2 Q92563-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000190
AC:
3
AN:
157870
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
83256
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000326
Gnomad OTH exome
AF:
0.000225
GnomAD4 exome
AF:
0.0000114
AC:
16
AN:
1401330
Hom.:
0
Cov.:
73
AF XY:
0.0000130
AC XY:
9
AN XY:
691480
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000279
Gnomad4 SAS exome
AF:
0.0000252
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000926
Gnomad4 OTH exome
AF:
0.0000516
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000584
Hom.:
0
Bravo
AF:
0.00000756
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1106G>A (p.R369H) alteration is located in exon 11 (coding exon 10) of the SPOCK2 gene. This alteration results from a G to A substitution at nucleotide position 1106, causing the arginine (R) at amino acid position 369 to be replaced by a histidine (H). 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
Benign
0.16
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
T;T;.
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Benign
0.084
D
MetaRNN
Pathogenic
0.87
D;D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Pathogenic
3.3
M;M;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-3.7
.;D;.
REVEL
Uncertain
0.46
Sift
Benign
0.044
.;D;.
Sift4G
Benign
0.068
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.81
MVP
0.56
MPC
1.1
ClinPred
0.96
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.58
gMVP
0.88

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: rs988182177; hg19: chr10-73822806; COSMIC: COSV100436318; API