20-2795673-C-G

Variant names:

• chr20-2795673-C-G
• rs764257542
• NM_019609.5:c.1646G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019609.5(CPXM1):​c.1646G>C​(p.Arg549Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R549L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPXM1 NM_019609.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 2 publications found

Genes affected

CPXM1 (HGNC:15771): (carboxypeptidase X, M14 family member 1) This gene likely encodes a member of the carboxypeptidase family of proteins. Cloning of a comparable locus in mouse indicates that the encoded protein contains a discoidin domain and a carboxypeptidase domain, but the protein appears to lack residues necessary for carboxypeptidase activity.[provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019609.5. 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
	CPXM1	NM_019609.5	MANE Select	c.1646G>C	p.Arg549Pro	missense	Exon 11 of 14	NP_062555.1	Q96SM3
	CPXM1	NM_001184699.2		c.1498+148G>C		intron	N/A	NP_001171628.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPXM1	ENST00000380605.3	TSL:1 MANE Select	c.1646G>C	p.Arg549Pro	missense	Exon 11 of 14	ENSP00000369979.2	Q96SM3
	CPXM1	ENST00000921882.1		c.1646G>C	p.Arg549Pro	missense	Exon 11 of 14	ENSP00000591941.1
	CPXM1	ENST00000867057.1		c.1637G>C	p.Arg546Pro	missense	Exon 11 of 14	ENSP00000537116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250920 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.23
Sift	Benign	0.20	T
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.48		Gain of glycosylation at R549 (P = 0.0488)
MVP		0.59
MPC		1.3
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.76
gMVP		0.90
Mutation Taster		=11/89	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: rs764257542; hg19: chr20-2776319;