chr12-75285073-T-C

Variant names:

• chr12-75285073-T-C
• NM_001355024.4:c.1289A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001355024.4(CAPS2):​c.1289A>G​(p.Glu430Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPS2 NM_001355024.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

Genes affected

CAPS2 (HGNC:16471): (calcyphosine 2) Calcyphosine-2 is a calcium-binding protein with 2 EF-hand motifs (Wang et al., 2002 [PubMed 11846421]).[supplied by OMIM, Mar 2008]

CAPS2-AS1 (HGNC:40769): (CAPS2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355024.4. 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
	CAPS2	NM_001355024.4	MANE Select	c.1289A>G	p.Glu430Gly	missense	Exon 15 of 17	NP_001341953.2	Q9BXY5-4
	CAPS2	NM_001355023.4		c.1307A>G	p.Glu436Gly	missense	Exon 16 of 18	NP_001341952.2
	CAPS2	NM_032606.5		c.1460A>G	p.Glu487Gly	missense	Exon 16 of 18	NP_115995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPS2	ENST00000699294.1	MANE Select	c.1289A>G	p.Glu430Gly	missense	Exon 15 of 17	ENSP00000514274.1	Q9BXY5-4
	CAPS2	ENST00000393284.8	TSL:1	c.1403A>G	p.Glu468Gly	missense	Exon 15 of 17	ENSP00000376963.4	Q9BXY5-5
	CAPS2	ENST00000409799.6	TSL:1	c.1193A>G	p.Glu398Gly	missense	Exon 14 of 16	ENSP00000386977.2	B9A061

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454492 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723442

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.0000232 AC: 1 AN: 43036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39290

South Asian (SAS) AF: 0.00 AC: 0 AN: 84494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109536

Other (OTH) AF: 0.0000166 AC: 1 AN: 60076

GnomAD4 genome Cov.: 32

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	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.7
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.89	P
Vest4		0.68
MutPred		0.54		Loss of ubiquitination at K484 (P = 0.0705)
MVP		0.88
MPC		0.23
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.32
gMVP		0.55
Mutation Taster		=41/59	disease causing

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

hg19: chr12-75678853;