chr12-68859062-C-A

Variant names:

• chr12-68859062-C-A
• rs769504248
• NM_198320.5:c.950G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198320.5(CPM):​c.950G>T​(p.Gly317Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000747 in 1,339,284 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G317D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CPM NM_198320.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198320.5. 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
	CPM	NM_198320.5	MANE Select	c.950G>T	p.Gly317Val	missense	Exon 8 of 9	NP_938079.1	P14384
	CPM	NM_001413387.1		c.986G>T	p.Gly329Val	missense	Exon 8 of 9	NP_001400316.1
	CPM	NM_001005502.3		c.950G>T	p.Gly317Val	missense	Exon 8 of 9	NP_001005502.1	P14384

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPM	ENST00000551568.6	TSL:1 MANE Select	c.950G>T	p.Gly317Val	missense	Exon 8 of 9	ENSP00000448517.1	P14384
	CPM	ENST00000338356.7	TSL:1	c.950G>T	p.Gly317Val	missense	Exon 7 of 8	ENSP00000339157.3	P14384
	CPM	ENST00000546373.5	TSL:1	c.950G>T	p.Gly317Val	missense	Exon 8 of 9	ENSP00000447255.1	P14384

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339284 Hom.: 0 Cov.: 28 AF XY: 0.00000151 AC XY: 1 AN XY: 663020

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28554

American (AMR) AF: 0.00 AC: 0 AN: 27914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22306

East Asian (EAS) AF: 0.00 AC: 0 AN: 35340

South Asian (SAS) AF: 0.0000165 AC: 1 AN: 60614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4436

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056534

Other (OTH) AF: 0.00 AC: 0 AN: 54574

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.73		Gain of catalytic residue at L313 (P = 0.0018)
MVP		0.92
MPC		1.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.98
Mutation Taster		=13/87	disease causing

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: rs769504248; hg19: chr12-69252842;