12-68869343-A-G

Variant names:

• chr12-68869343-A-G
• rs1006581715
• NM_198320.5:c.769T>C

Variant summary

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

The NM_198320.5(CPM):​c.769T>C​(p.Ser257Pro) 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. 13/22 in silico tools predict 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. S257T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPM NM_198320.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• 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: 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=0.28830332).

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.769T>C	p.Ser257Pro	missense	Exon 6 of 9	NP_938079.1	P14384
	CPM	NM_001413387.1		c.805T>C	p.Ser269Pro	missense	Exon 6 of 9	NP_001400316.1
	CPM	NM_001005502.3		c.769T>C	p.Ser257Pro	missense	Exon 6 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.769T>C	p.Ser257Pro	missense	Exon 6 of 9	ENSP00000448517.1	P14384
	CPM	ENST00000338356.7	TSL:1	c.769T>C	p.Ser257Pro	missense	Exon 5 of 8	ENSP00000339157.3	P14384
	CPM	ENST00000546373.5	TSL:1	c.769T>C	p.Ser257Pro	missense	Exon 6 of 9	ENSP00000447255.1	P14384

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.033
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Benign	0.031	D
Sift4G	Benign	0.23	T
Polyphen		0.84	P
Vest4		0.49
MutPred		0.60		Gain of catalytic residue at W258 (P = 0.001)
MVP		0.27
MPC		1.1
ClinPred		0.91	D
GERP RS		-0.20
Varity_R		0.87
gMVP		0.93
Mutation Taster		=64/36	polymorphism

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: rs1006581715; hg19: chr12-69263123;