16-12664961-G-C

Variant names:

• chr16-12664961-G-C
• rs1596435000
• NM_018340.3:c.870C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018340.3(CPPED1):​c.870C>G​(p.His290Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,906 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H290P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CPPED1 NM_018340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.235

Genes affected

CPPED1 (HGNC:25632): (calcineurin like phosphoesterase domain containing 1) Predicted to enable metal ion binding activity; protein serine phosphatase activity; and protein threonine phosphatase activity. Predicted to be involved in protein dephosphorylation. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPPED1	NM_018340.3	c.870C>G	p.His290Gln	missense_variant	Exon 4 of 4	ENST00000381774.9	NP_060810.2
CPPED1	NM_001099455.2	c.444C>G	p.His148Gln	missense_variant	Exon 3 of 3		NP_001092925.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPPED1	ENST00000381774.9	c.870C>G	p.His290Gln	missense_variant	Exon 4 of 4	1	NM_018340.3	ENSP00000371193.4
CPPED1	ENST00000433677.6	c.444C>G	p.His148Gln	missense_variant	Exon 3 of 3	1		ENSP00000411127.2
CPPED1	ENST00000261660.4	c.349C>G	p.Pro117Ala	missense_variant	Exon 3 of 3	2		ENSP00000261660.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458906 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 725934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.870C>G (p.H290Q) alteration is located in exon 4 (coding exon 4) of the CPPED1 gene. This alteration results from a C to G substitution at nucleotide position 870, causing the histidine (H) at amino acid position 290 to be replaced by a glutamine (Q). 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	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.066	T;D
Sift4G	Benign	0.061	T;D
Polyphen		0.98	D;D
Vest4		0.82
MutPred		0.78		Gain of helix (P = 0.0325);.;
MVP		0.49
MPC		0.33
ClinPred		1.0	D
GERP RS		-4.8
Varity_R		0.44
gMVP		0.45

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: rs1596435000; hg19: chr16-12758818;