10-123746804-C-G

Variant names:

• chr10-123746804-C-G
• rs149753704
• NM_198148.3:c.2231G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198148.3(CPXM2):​c.2231G>C​(p.Arg744Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,614,228 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. R744W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: CPXM2 NM_198148.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18
• Publications: 9 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056640774).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPXM2	NM_198148.3	c.2231G>C	p.Arg744Pro	missense_variant	Exon 14 of 14	ENST00000241305.4	NP_937791.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPXM2	ENST00000241305.4	c.2231G>C	p.Arg744Pro	missense_variant	Exon 14 of 14	1	NM_198148.3	ENSP00000241305.3
CPXM2	ENST00000615851.4	c.505+7859G>C		intron_variant	Intron 13 of 14	5		ENSP00000483180.1
CPXM2	ENST00000368854.7	n.2064+7859G>C		intron_variant	Intron 15 of 19	2

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000609 AC: 153 AN: 251410 AF XY: 0.000559

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000787 AC: 1150 AN: 1461874 Hom.: 2 Cov.: 35 AF XY: 0.000787 AC XY: 572 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000948 AC: 1054 AN: 1111996

Other (OTH) AF: 0.000546 AC: 33 AN: 60396

GnomAD4 genome AF: 0.000459 AC: 70 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68038

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2231G>C (p.R744P) alteration is located in exon 14 (coding exon 14) of the CPXM2 gene. This alteration results from a G to C substitution at nucleotide position 2231, causing the arginine (R) at amino acid position 744 to be replaced by a proline (P). 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	0.14
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0059	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.057	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.54
Sift	Benign	0.13	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.30
MVP		0.98
MPC		0.28
ClinPred		0.033	T
GERP RS		3.1
Varity_R		0.27
gMVP		0.80
Mutation Taster		=84/16	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: rs149753704; hg19: chr10-125506320;