Genetic Variant NM_198320.5:c.950G>A (chr12-68859062-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198320.5(CPM):c.950G>A(p.Gly317Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,491,084 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. G317V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

CPM
NM_198320.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Publications

0 publications found

Variant links:

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]

CPM links:

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ACMG classification

Classification was made for transcript

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, 0.94

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPM	NM_198320.5	MANE Select	c.950G>A	p.Gly317Asp	missense	Exon 8 of 9	NP_938079.1	P14384
CPM	NM_001413387.1		c.986G>A	p.Gly329Asp	missense	Exon 8 of 9	NP_001400316.1
CPM	NM_001005502.3		c.950G>A	p.Gly317Asp	missense	Exon 8 of 9	NP_001005502.1	P14384

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPM	ENST00000551568.6	TSL:1 MANE Select	c.950G>A	p.Gly317Asp	missense	Exon 8 of 9	ENSP00000448517.1	P14384
CPM	ENST00000338356.7	TSL:1	c.950G>A	p.Gly317Asp	missense	Exon 7 of 8	ENSP00000339157.3	P14384
CPM	ENST00000546373.5	TSL:1	c.950G>A	p.Gly317Asp	missense	Exon 8 of 9	ENSP00000447255.1	P14384

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000105

AC:

AN:

189582

AF XY:

0.0000191

show subpopulations

Gnomad AFR exome

AF:

0.0000779

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000672

AC:

AN:

1339284

Hom.:

Cov.:

AF XY:

0.00000754

AC XY:

AN XY:

663020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28554

American (AMR)

AF:

0.00

AC:

AN:

27914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22306

East Asian (EAS)

AF:

0.00

AC:

AN:

35340

South Asian (SAS)

AF:

0.00

AC:

AN:

60614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4436

European-Non Finnish (NFE)

AF:

0.00000852

AC:

AN:

1056534

Other (OTH)

AF:

0.00

AC:

AN:

54574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41354

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.0

PhyloP100

7.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.76

Gain of catalytic residue at L313 (P = 0.0021)

MVP

0.94

MPC

1.6

ClinPred

1.0

GERP RS

5.6

Varity_R

0.96

gMVP

0.99

Mutation Taster

=11/89

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over