12-68869360-C-G

Position:

• chr12-68869360-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198320.5(CPM):​c.752G>C​(p.Gly251Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,576 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPM NM_198320.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.29

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPM	NM_198320.5	c.752G>C	p.Gly251Ala	missense_variant	6/9	ENST00000551568.6	NP_938079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPM	ENST00000551568.6	c.752G>C	p.Gly251Ala	missense_variant	6/9	1	NM_198320.5	ENSP00000448517.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461576 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727070

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism Uncertain:1

Uncertain significance, no assertion criteria provided

research

Centre for Addiction & Mental Health, Centre for Addiction & Mental Health

-

Gene not previously associated with disease; independent supportng evidence needed -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.7	H;H;H
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.85
MutPred		0.74		Gain of catalytic residue at Y256 (P = 0.0091);Gain of catalytic residue at Y256 (P = 0.0091);Gain of catalytic residue at Y256 (P = 0.0091);
MVP		0.50
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.95

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: chr12-69263140;