16-12664990-C-G

Variant names:

• chr16-12664990-C-G
• rs374948695
• NM_018340.3:c.841G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018340.3(CPPED1):​c.841G>C​(p.Val281Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V281M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CPPED1 NM_018340.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27744716).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018340.3. 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
	CPPED1	NM_018340.3	MANE Select	c.841G>C	p.Val281Leu	missense	Exon 4 of 4	NP_060810.2	Q9BRF8-1
	CPPED1	NM_001099455.2		c.415G>C	p.Val139Leu	missense	Exon 3 of 3	NP_001092925.1	Q9BRF8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPPED1	ENST00000381774.9	TSL:1 MANE Select	c.841G>C	p.Val281Leu	missense	Exon 4 of 4	ENSP00000371193.4	Q9BRF8-1
	CPPED1	ENST00000433677.6	TSL:1	c.415G>C	p.Val139Leu	missense	Exon 3 of 3	ENSP00000411127.2	Q9BRF8-2
	CPPED1	ENST00000898262.1		c.886G>C	p.Val296Leu	missense	Exon 5 of 5	ENSP00000568321.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246852 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459450 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726112

African (AFR) AF: 0.00 AC: 0 AN: 33222

American (AMR) AF: 0.0000228 AC: 1 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111144

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.28	T
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.7
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.23
MutPred		0.26		Loss of MoRF binding (P = 4e-04)
MVP		0.43
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.62

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: rs374948695; hg19: chr16-12758847;