rs192611362

Variant names:

• chr1-233179093-C-T
• rs192611362
• NM_014801.4:c.3149G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

The NM_014801.4(PCNX2):​c.3149G>A​(p.Arg1050His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,613,758 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (2 hom.)
• Consequence: PCNX2 NM_014801.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

Genes affected

PCNX2 (HGNC:8736): (pecanex 2) This gene contains coding mononucleotide repeats that are associated with tumors of high mcrosatellite instability (MSI-H). Defects in this gene are involved in the tumorigenesis of MSI-H colorectal carcinomas. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.04483214).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNX2	NM_014801.4	c.3149G>A	p.Arg1050His	missense_variant	Exon 16 of 34	ENST00000258229.14	NP_055616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNX2	ENST00000258229.14	c.3149G>A	p.Arg1050His	missense_variant	Exon 16 of 34	5	NM_014801.4	ENSP00000258229.8

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000735 AC: 183 AN: 249046 Hom.: 0 AF XY: 0.000681 AC XY: 92 AN XY: 135116

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000833

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000853 AC: 1246 AN: 1461476 Hom.: 2 Cov.: 30 AF XY: 0.000840 AC XY: 611 AN XY: 727024

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000896

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74450

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000982 Hom.: 0

Bravo AF: 0.000997

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.000776 AC: 94

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3149G>A (p.R1050H) alteration is located in exon 16 (coding exon 16) of the PCNX2 gene. This alteration results from a G to A substitution at nucleotide position 3149, causing the arginine (R) at amino acid position 1050 to be replaced by a histidine (H). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MVP		0.73
MPC		0.68
ClinPred		0.11	T
GERP RS		5.7
Varity_R		0.51
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs192611362; hg19: chr1-233314839; COSMIC: COSV50822032; COSMIC: COSV50822032;