10-72063097-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001244950.2(SPOCK2):c.1057G>A(p.Gly353Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,555,236 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (32 hom.)
• Consequence: SPOCK2 NM_001244950.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058939457).
• BP6: Variant 10-72063097-C-T is Benign according to our data. Variant chr10-72063097-C-T is described in ClinVar as [Benign]. Clinvar id is 773516.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00436 (6115/1402904) while in subpopulation EAS AF= 0.0229 (821/35924). AF 95% confidence interval is 0.0216. There are 32 homozygotes in gnomad4_exome. There are 3070 alleles in male gnomad4_exome subpopulation. Median coverage is 75. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK2	NM_001244950.2	c.1057G>A	p.Gly353Ser	missense_variant	10/11	ENST00000373109.7
SPOCK2	NM_014767.2	c.1057G>A	p.Gly353Ser	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK2	ENST00000373109.7	c.1057G>A	p.Gly353Ser	missense_variant	10/11	1	NM_001244950.2	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152214 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00412 AC: 666 AN: 161710 Hom.: 2 AF XY: 0.00428 AC XY: 365 AN XY: 85192

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00593

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.0000638

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.00436 AC: 6115 AN: 1402904 Hom.: 32 Cov.: 75 AF XY: 0.00443 AC XY: 3070 AN XY: 692298

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.00468

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.000344

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00622

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152332 Hom.: 2 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74494

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00406 Hom.: 5

Bravo AF: 0.00391

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.00317 AC: 27

ExAC AF: 0.00229 AC: 260

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Uncertain	0.013	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
REVEL	Uncertain	0.53
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.74
MVP		0.64
MPC		0.96
ClinPred		0.015	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2306322; hg19: chr10-73822855; COSMIC: COSV58037519;