chr4-1170431-C-T

Variant names:

• chr4-1170431-C-T
• rs200761543
• NM_012445.4:c.782G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 14/20 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.597
• Publications: 0 publications found

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]

LOC124900647 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00499776).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012445.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPON2	NM_012445.4	MANE Select	c.782G>A	p.Arg261Lys	missense	Exon 5 of 6	NP_036577.2	Q9BUD6
	SPON2	NM_001128325.3		c.782G>A	p.Arg261Lys	missense	Exon 6 of 7	NP_001121797.2	Q9BUD6
	SPON2	NM_001199021.2		c.782G>A	p.Arg261Lys	missense	Exon 7 of 8	NP_001185950.2	Q9BUD6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPON2	ENST00000290902.10	TSL:1 MANE Select	c.782G>A	p.Arg261Lys	missense	Exon 5 of 6	ENSP00000290902.5	Q9BUD6
	SPON2	ENST00000960395.1		c.1106G>A	p.Arg369Lys	missense	Exon 5 of 6	ENSP00000630454.1
	SPON2	ENST00000431380.5	TSL:5	c.782G>A	p.Arg261Lys	missense	Exon 6 of 7	ENSP00000394832.1	Q9BUD6

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152210 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000168 AC: 42 AN: 250354 AF XY: 0.000103

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 118 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111914

Other (OTH) AF: 0.000149 AC: 9 AN: 60374

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000219 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Benign	-0.94	T
PhyloP100		0.60
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.045
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Vest4		0.050
MVP		0.32
MPC		0.25
ClinPred		0.098	T
GERP RS		2.7
gMVP		0.36
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200761543; hg19: chr4-1164219;