12-68866971-G-C

Position:

• chr12-68866971-G-C

Variant summary

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

The NM_198320.5(CPM):​c.865C>G​(p.Arg289Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPM NM_198320.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

CPM (HGNC:2311): (carboxypeptidase M) The protein encoded by this gene is a membrane-bound arginine/lysine carboxypeptidase. Its expression is associated with monocyte to macrophage differentiation. This encoded protein contains hydrophobic regions at the amino and carboxy termini and has 6 potential asparagine-linked glycosylation sites. The active site residues of carboxypeptidases A and B are conserved in this protein. Three alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPM	NM_198320.5	c.865C>G	p.Arg289Gly	missense_variant	7/9	ENST00000551568.6	NP_938079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPM	ENST00000551568.6	c.865C>G	p.Arg289Gly	missense_variant	7/9	1	NM_198320.5	ENSP00000448517.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 05, 2022

The c.865C>G (p.R289G) alteration is located in exon 7 (coding exon 6) of the CPM gene. This alteration results from a C to G substitution at nucleotide position 865, causing the arginine (R) at amino acid position 289 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	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;D;.
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.35
MutPred		0.47		Gain of ubiquitination at K292 (P = 0.0432);Gain of ubiquitination at K292 (P = 0.0432);Gain of ubiquitination at K292 (P = 0.0432);
MVP		0.39
MPC		0.70
ClinPred		0.43	T
GERP RS		3.6
Varity_R		0.27
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 0

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: chr12-69260751;