12-68858996-T-A

Variant names:

• chr12-68858996-T-A
• rs147258017
• NM_198320.5:c.1016A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198320.5(CPM):​c.1016A>T​(p.His339Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,423,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H339Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CPM NM_198320.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• 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 2 ACMG points.

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

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.1016A>T	p.His339Leu	missense	Exon 8 of 9	NP_938079.1	P14384
	CPM	NM_001413387.1		c.1052A>T	p.His351Leu	missense	Exon 8 of 9	NP_001400316.1
	CPM	NM_001005502.3		c.1016A>T	p.His339Leu	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.1016A>T	p.His339Leu	missense	Exon 8 of 9	ENSP00000448517.1	P14384
	CPM	ENST00000338356.7	TSL:1	c.1016A>T	p.His339Leu	missense	Exon 7 of 8	ENSP00000339157.3	P14384
	CPM	ENST00000546373.5	TSL:1	c.1016A>T	p.His339Leu	missense	Exon 8 of 9	ENSP00000447255.1	P14384

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423684 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 707660

African (AFR) AF: 0.00 AC: 0 AN: 31886

American (AMR) AF: 0.00 AC: 0 AN: 40786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 37484

South Asian (SAS) AF: 0.00 AC: 0 AN: 78960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092984

Other (OTH) AF: 0.00 AC: 0 AN: 58590

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.028	D
Polyphen		0.18	B
Vest4		0.57
MutPred		0.58		Gain of catalytic residue at Q335 (P = 4e-04)
MVP		0.76
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.89
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147258017; hg19: chr12-69252776;