10-72062887-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001244950.2(SPOCK2):c.1148C>T(p.Ser383Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,598,998 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 (★). Synonymous variant affecting the same amino acid position (i.e. S383S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SPOCK2 NM_001244950.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a glycosylation_site O-linked (Xyl...) (glycosaminoglycan) serine (size 0) in uniprot entity TICN2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23496735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOCK2	NM_001244950.2	c.1148C>T	p.Ser383Leu	missense_variant	11/11	ENST00000373109.7
SPOCK2	NM_014767.2	c.1148C>T	p.Ser383Leu	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOCK2	ENST00000373109.7	c.1148C>T	p.Ser383Leu	missense_variant	11/11	1	NM_001244950.2	P1
SPOCK2	ENST00000317376.8	c.1148C>T	p.Ser383Leu	missense_variant	12/12	1		P1
SPOCK2	ENST00000463279.6	n.716C>T		non_coding_transcript_exon_variant	7/7	5
SPOCK2	ENST00000469121.5	n.784C>T		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151738 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 35 AN: 227664 Hom.: 0 AF XY: 0.000122 AC XY: 15 AN XY: 123270

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00124

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 266 AN: 1447260 Hom.: 0 Cov.: 73 AF XY: 0.000167 AC XY: 120 AN XY: 719288

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00123

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151738 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 13 AN XY: 74070

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

The c.1148C>T (p.S383L) 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 1148, causing the serine (S) at amino acid position 383 to be replaced by a leucine (L). 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	Pathogenic	0.64
BayesDel_addAF	Benign	0.0092	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.81	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
REVEL	Uncertain	0.46
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.74
MutPred		0.35		Loss of glycosylation at S383 (P = 0.0018);Loss of glycosylation at S383 (P = 0.0018);.;
MVP		0.29
MPC		0.25
ClinPred		0.35	T
GERP RS		5.3
Varity_R		0.55
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs199837517; hg19: chr10-73822645;