10-123761881-C-T

Variant names:

• chr10-123761881-C-T
• rs749448782
• NM_198148.3:c.1768G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198148.3(CPXM2):​c.1768G>A​(p.Val590Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,613,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (1 hom.)
• Consequence: CPXM2 NM_198148.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14
• Publications: 2 publications found

Genes affected

CPXM2 (HGNC:26977): (carboxypeptidase X, M14 family member 2) Predicted to enable metallocarboxypeptidase activity. Predicted to be involved in peptide metabolic process and protein processing. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000231138 (HGNC:58377):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19688544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPXM2	NM_198148.3	c.1768G>A	p.Val590Ile	missense_variant	Exon 11 of 14	ENST00000241305.4	NP_937791.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPXM2	ENST00000241305.4	c.1768G>A	p.Val590Ile	missense_variant	Exon 11 of 14	1	NM_198148.3	ENSP00000241305.3
CPXM2	ENST00000615851.4	c.256G>A	p.Val86Ile	missense_variant	Exon 11 of 15	5		ENSP00000483180.1
CPXM2	ENST00000368854.7	n.1815G>A		non_coding_transcript_exon_variant	Exon 13 of 20	2
ENSG00000231138	ENST00000818156.1	n.142+595C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248298 AF XY: 0.0000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1460976 Hom.: 1 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 726756

African (AFR) AF: 0.000120 AC: 4 AN: 33464

American (AMR) AF: 0.0000896 AC: 4 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111706

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1768G>A (p.V590I) alteration is located in exon 11 (coding exon 11) of the CPXM2 gene. This alteration results from a G to A substitution at nucleotide position 1768, causing the valine (V) at amino acid position 590 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.89	.;L
PhyloP100		6.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.57	.;N
REVEL	Benign	0.20
Sift	Benign	0.15	.;T
Sift4G	Benign	0.23	T;T
Polyphen		0.12	.;B
Vest4		0.43
MVP		0.38
MPC		0.30
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.066
gMVP		0.36
Mutation Taster		=93/7	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: rs749448782; hg19: chr10-125521397; COSMIC: COSV53871867;