4-1170431-C-T

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

1
15

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]

Genome browser will be placed here

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
SPON2NM_012445.4 linkc.782G>A p.Arg261Lys missense_variant Exon 5 of 6 ENST00000290902.10 NP_036577.2 Q9BUD6
SPON2NM_001128325.3 linkc.782G>A p.Arg261Lys missense_variant Exon 6 of 7 NP_001121797.2 Q9BUD6
SPON2NM_001199021.2 linkc.782G>A p.Arg261Lys missense_variant Exon 7 of 8 NP_001185950.2 Q9BUD6
LOC124900647XM_047416477.1 linkc.-2486-20669C>T intron_variant Intron 1 of 2 XP_047272433.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPON2ENST00000290902.10 linkc.782G>A p.Arg261Lys missense_variant Exon 5 of 6 1 NM_012445.4 ENSP00000290902.5 Q9BUD6
SPON2ENST00000431380.5 linkc.782G>A p.Arg261Lys missense_variant Exon 6 of 7 5 ENSP00000394832.1 Q9BUD6
SPON2ENST00000617421.4 linkc.782G>A p.Arg261Lys missense_variant Exon 7 of 8 5 ENSP00000483599.1 Q9BUD6
SPON2ENST00000509697.1 linkn.218G>A non_coding_transcript_exon_variant Exon 2 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152210
Hom.:
0
Cov.:
33
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:
42
AN:
250354
Hom.:
0
AF XY:
0.000103
AC XY:
14
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.:
0
Cov.:
30
AF XY:
0.0000949
AC XY:
69
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:
22
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
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.:
0
Bravo
AF:
0.000121
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000148
AC:
18
Asia WGS
AF:
0.000289
AC:
2
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
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
11
DANN
Benign
0.73
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.28
N
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.0050
T;T;T
MetaSVM
Benign
-0.94
T
PrimateAI
Uncertain
0.50
T
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
T
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.

Other links and lift over

dbSNP: rs200761543; hg19: chr4-1164219; API