16-12704990-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018340.3(CPPED1):c.349A>G(p.Arg117Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPPED1 NM_018340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11275509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPPED1	NM_018340.3	c.349A>G	p.Arg117Gly	missense_variant	3/4	ENST00000381774.9
CPPED1	NM_001099455.2	c.290-39875A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPPED1	ENST00000381774.9	c.349A>G	p.Arg117Gly	missense_variant	3/4	1	NM_018340.3	P1
CPPED1	ENST00000433677.6	c.290-39875A>G		intron_variant		1
CPPED1	ENST00000261660.4	c.290-39970A>G		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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: 8.99e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

The c.349A>G (p.R117G) alteration is located in exon 3 (coding exon 3) of the CPPED1 gene. This alteration results from a A to G substitution at nucleotide position 349, causing the arginine (R) at amino acid position 117 to be replaced by a glycine (G). 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	0.062
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.77
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.91
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.80	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.24	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.48		Loss of MoRF binding (P = 0.0203);
MVP		0.32
MPC		0.064
ClinPred		0.097	T
GERP RS		0.26
Varity_R		0.057
gMVP		0.28

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: rs2080041973; hg19: chr16-12798847;