dbSNP rs775714079: SPOCK2:p.Asp338Tyr (chr10-72063142-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001244950.2(SPOCK2):c.1012G>T(p.Asp338Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D338N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SPOCK2
NM_001244950.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.77

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOCK2	NM_001244950.2 link	c.1012G>T	p.Asp338Tyr	missense_variant	Exon 10 of 11	ENST00000373109.7	NP_001231879.1	Q92563-1
SPOCK2	NM_014767.2 link	c.1012G>T	p.Asp338Tyr	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.1012G>T	p.Asp338Tyr	missense_variant	Exon 10 of 11	1	NM_001244950.2	ENSP00000362201.2		Q92563-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404538

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31792

American (AMR)

AF:

0.00

AC:

AN:

36508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

36064

South Asian (SAS)

AF:

0.00

AC:

AN:

79484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1081868

Other (OTH)

AF:

0.00

AC:

AN:

58230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;T;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.9

H;H;.

PhyloP100

2.8

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.9

.;D;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

.;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.80

MutPred

0.73

Loss of disorder (P = 0.0398);Loss of disorder (P = 0.0398);.;

MVP

0.75

MPC

1.1

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.88

Mutation Taster

=10/90

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over