3-194341097-C-T

Variant names:

• chr3-194341097-C-T
• rs11711157
• NM_001080513.4:c.1606G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080513.4(CPN2):​c.1606G>A​(p.Val536Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,607,610 control chromosomes in the GnomAD database, including 66,914 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (5399 hom., cov: 33)
  • Exomes 𝑓: 0.29 (61515 hom.)
• Consequence: CPN2 NM_001080513.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.528

Genes affected

CPN2 (HGNC:2313): (carboxypeptidase N subunit 2) Predicted to be involved in regulation of catalytic activity. Located in blood microparticle and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004115194).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPN2	NM_001080513.4	c.1606G>A	p.Val536Met	missense_variant	Exon 2 of 2	ENST00000323830.4	NP_001073982.3
CPN2	NM_001291988.2	c.1606G>A	p.Val536Met	missense_variant	Exon 2 of 2		NP_001278917.1
CPN2	XM_005269280.5	c.1606G>A	p.Val536Met	missense_variant	Exon 3 of 3		XP_005269337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPN2	ENST00000323830.4	c.1606G>A	p.Val536Met	missense_variant	Exon 2 of 2	1	NM_001080513.4	ENSP00000319464.3
CPN2	ENST00000429275.1	c.1606G>A	p.Val536Met	missense_variant	Exon 2 of 2	5		ENSP00000402232.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39503 AN: 152070 Hom.: 5401 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.254

GnomAD3 exomes AF: 0.289 AC: 71781 AN: 248410 Hom.: 11056 AF XY: 0.297 AC XY: 39974 AN XY: 134492

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.399

Gnomad FIN exome AF: 0.354

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.287 AC: 417851 AN: 1455422 Hom.: 61515 Cov.: 34 AF XY: 0.291 AC XY: 210203 AN XY: 722926

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.260 AC: 39505 AN: 152188 Hom.: 5399 Cov.: 33 AF XY: 0.265 AC XY: 19729 AN XY: 74416

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.244

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.257

Alfa AF: 0.279 Hom.: 15114

Bravo AF: 0.243

TwinsUK AF: 0.285 AC: 1057

ALSPAC AF: 0.287 AC: 1106

ESP6500AA AF: 0.187 AC: 822

ESP6500EA AF: 0.280 AC: 2409

ExAC AF: 0.288 AC: 34997

Asia WGS AF: 0.365 AC: 1271 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	.;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.074
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.92	P;P
Vest4		0.087
MPC		0.37
ClinPred		0.0092	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs11711157; hg19: chr3-194061826; COSMIC: COSV60469475;