Genetic Variant NM_001244950.2:c.1255G>A (chr10-72062780-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001244950.2(SPOCK2):c.1255G>A(p.Asp419Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,607,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SPOCK2
NM_001244950.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOCK2	NM_001244950.2 link	c.1255G>A	p.Asp419Asn	missense_variant	Exon 11 of 11	ENST00000373109.7	NP_001231879.1	Q92563-1
SPOCK2	NM_014767.2 link	c.1255G>A	p.Asp419Asn	missense_variant	Exon 12 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.1255G>A	p.Asp419Asn	missense_variant	Exon 11 of 11	1	NM_001244950.2	ENSP00000362201.2		Q92563-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246912

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000962

AC:

AN:

1455246

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.0000226

AC:

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111636

Other (OTH)

AF:

0.0000664

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.000196

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1255G>A (p.D419N) alteration is located in exon 12 (coding exon 11) of the SPOCK2 gene. This alteration results from a G to A substitution at nucleotide position 1255, causing the aspartic acid (D) at amino acid position 419 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

.;T;T

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.81

L;L;.

PhyloP100

7.3

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

.;N;D

REVEL

Benign

0.26

Sift

Pathogenic

0.0

.;D;D

Sift4G

Benign

0.068

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.63

MutPred

0.17

Loss of phosphorylation at Y422 (P = 0.0897);Loss of phosphorylation at Y422 (P = 0.0897);.;

MVP

0.69

MPC

0.27

ClinPred

0.85

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.69

Mutation Taster

=71/29

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.1255G>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