Genetic Variant NM_001244950.2:c.1123G>A (chr10-72063031-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001244950.2(SPOCK2):c.1123G>A(p.Asp375Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,556,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

SPOCK2
NM_001244950.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Publications

0 publications found

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]

SPOCK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046572268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOCK2	NM_001244950.2 link	c.1123G>A	p.Asp375Asn	missense_variant	Exon 10 of 11	ENST00000373109.7	NP_001231879.1	Q92563-1
SPOCK2	NM_014767.2 link	c.1123G>A	p.Asp375Asn	missense_variant	Exon 11 of 12		NP_055582.1	Q92563-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOCK2	ENST00000373109.7 link	c.1123G>A	p.Asp375Asn	missense_variant	Exon 10 of 11	1	NM_001244950.2	ENSP00000362201.2		Q92563-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

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:

0.000478

GnomAD2 exomes

AF:

0.000137

AC:

AN:

160268

AF XY:

0.0000825

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.000237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000698

AC:

AN:

1404510

Hom.:

Cov.:

AF XY:

0.0000577

AC XY:

AN XY:

693544

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

31828

American (AMR)

AF:

0.000274

AC:

AN:

36480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36142

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49026

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1082162

Other (OTH)

AF:

0.000240

AC:

AN:

58238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000407

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

41578

American (AMR)

AF:

0.000849

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000510

Hom.:

Bravo

AF:

0.000661

ESP6500AA

AF:

0.00161

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000612

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1123G>A (p.D375N) 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 1123, causing the aspartic acid (D) at amino acid position 375 to be replaced by an asparagine (N). 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

0.072

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

T;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.3

L;L;.

PhyloP100

1.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.97

N;N;.

REVEL

Benign

0.26

Sift

Benign

0.39

T;T;.

Sift4G

Benign

0.37

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.14

MVP

0.57

MPC

0.92

ClinPred

0.055

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.70

Mutation Taster

=62/38

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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NM_001244950.2:c.1123G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over