Genetic Variant NM_001244950.2:c.1199C>T (chr10-72062836-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001244950.2(SPOCK2):c.1199C>T(p.Thr400Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,456,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SPOCK2
NM_001244950.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07880357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOCK2	NM_001244950.2 link	c.1199C>T	p.Thr400Met	missense_variant	Exon 11 of 11	ENST00000373109.7	NP_001231879.1	Q92563-1
SPOCK2	NM_014767.2 link	c.1199C>T	p.Thr400Met	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.1199C>T	p.Thr400Met	missense_variant	Exon 11 of 11	1	NM_001244950.2	ENSP00000362201.2		Q92563-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000496

AC:

AN:

242062

AF XY:

0.0000533

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1456180

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

724386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.0000452

AC:

AN:

44274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.000221

AC:

AN:

85910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110788

Other (OTH)

AF:

0.0000166

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1199C>T (p.T400M) alteration is located in exon 12 (coding exon 11) of the SPOCK2 gene. This alteration results from a C to T substitution at nucleotide position 1199, causing the threonine (T) at amino acid position 400 to be replaced by a methionine (M). 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

0.077

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.081

T;T;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.079

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

6.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.070

Sift

Benign

0.12

.;T;.

Sift4G

Benign

0.12

T;T;T

Polyphen

0.56

P;P;.

Vest4

0.14

MutPred

0.20

Loss of phosphorylation at T400 (P = 0.0143);Loss of phosphorylation at T400 (P = 0.0143);.;

MVP

0.18

MPC

0.29

ClinPred

0.16

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.087

gMVP

0.38

Mutation Taster

=86/14

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.1199C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over