16-12781247-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018340.3(CPPED1):c.227A>G(p.Asn76Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CPPED1 NM_018340.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPPED1	NM_018340.3	c.227A>G	p.Asn76Ser	missense_variant	2/4	ENST00000381774.9
CPPED1	NM_001099455.2	c.227A>G	p.Asn76Ser	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPPED1	ENST00000381774.9	c.227A>G	p.Asn76Ser	missense_variant	2/4	1	NM_018340.3	P1
CPPED1	ENST00000433677.6	c.227A>G	p.Asn76Ser	missense_variant	2/3	1
CPPED1	ENST00000261660.4	c.227A>G	p.Asn76Ser	missense_variant	2/3	2
CPPED1	ENST00000539677.1	n.295A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 12, 2023

The c.227A>G (p.N76S) alteration is located in exon 2 (coding exon 2) of the CPPED1 gene. This alteration results from a A to G substitution at nucleotide position 227, causing the asparagine (N) at amino acid position 76 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;T;D
Polyphen		0.99	D;D;.
Vest4		0.49
MutPred		0.73		Gain of catalytic residue at K77 (P = 0.0084);Gain of catalytic residue at K77 (P = 0.0084);Gain of catalytic residue at K77 (P = 0.0084);
MVP		0.65
MPC		0.32
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-12875104;