Genetic Variant SPON2:p.Arg261Lys (chr4-1170431-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012445.4(SPON2):c.782G>A(p.Arg261Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

SPON2
NM_012445.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.597

Variant links:

Genes affected

SPON2 (HGNC:11253): (spondin 2) Predicted to enable antigen binding activity; lipopolysaccharide binding activity; and metal ion binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within several processes, including defense response to other organism; opsonization; and positive regulation of cytokine production. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SPON2 links:

LOC124900647 (HGNC:):

LOC124900647 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00499776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPON2	NM_012445.4 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 5 of 6	ENST00000290902.10	NP_036577.2	Q9BUD6
SPON2	NM_001128325.3 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 6 of 7		NP_001121797.2	Q9BUD6
SPON2	NM_001199021.2 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 7 of 8		NP_001185950.2	Q9BUD6
LOC124900647	XM_047416477.1 link	c.-2486-20669C>T		intron_variant	Intron 1 of 2		XP_047272433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPON2	ENST00000290902.10 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 5 of 6	1	NM_012445.4	ENSP00000290902.5	Q9BUD6
SPON2	ENST00000431380.5 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 6 of 7	5		ENSP00000394832.1	Q9BUD6
SPON2	ENST00000617421.4 link	c.782G>A	p.Arg261Lys	missense_variant	Exon 7 of 8	5		ENSP00000483599.1	Q9BUD6
SPON2	ENST00000509697.1 link	n.218G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

250354

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000965

AC:

141

AN:

1461538

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00452

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000145

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782G>A (p.R261K) alteration is located in exon 7 (coding exon 4) of the SPON2 gene. This alteration results from a G to A substitution at nucleotide position 782, causing the arginine (R) at amino acid position 261 to be replaced by a lysine (K). 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

0.087

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.73

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.28

M_CAP

Benign

0.018

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.94

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.31

N;N;.

REVEL

Benign

0.045

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.98

T;T;T

Vest4

0.050

MVP

0.32

MPC

0.25

ClinPred

0.098

GERP RS

2.7

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over