chr1-233000385-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014801.4(PCNX2):​c.5248C>T​(p.Arg1750Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PCNX2
NM_014801.4 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.717
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PCNX2NM_014801.4 linkuse as main transcriptc.5248C>T p.Arg1750Trp missense_variant 30/34 ENST00000258229.14 NP_055616.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PCNX2ENST00000258229.14 linkuse as main transcriptc.5248C>T p.Arg1750Trp missense_variant 30/345 NM_014801.4 ENSP00000258229 A2A6NKB5-1
PCNX2ENST00000344698.6 linkuse as main transcriptc.1204C>T p.Arg402Trp missense_variant 7/102 ENSP00000340759 P4A6NKB5-3
PCNX2ENST00000462233.5 linkuse as main transcriptc.*587C>T 3_prime_UTR_variant, NMD_transcript_variant 16/202 ENSP00000428488

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD3 exomes
AF:
0.0000283
AC:
7
AN:
247512
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134226
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000536
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1460028
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
726142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000496
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2021The c.5248C>T (p.R1750W) alteration is located in exon 30 (coding exon 30) of the PCNX2 gene. This alteration results from a C to T substitution at nucleotide position 5248, causing the arginine (R) at amino acid position 1750 to be replaced by a tryptophan (W). 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
0.53
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.42
T;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Uncertain
0.094
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
-0.045
T
MutationAssessor
Pathogenic
3.1
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.7
D;D
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.87
MutPred
0.84
Loss of disorder (P = 0.0563);.;
MVP
0.80
MPC
0.67
ClinPred
0.98
D
GERP RS
-0.98
Varity_R
0.82
gMVP
0.81

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs528200127; hg19: chr1-233136131; COSMIC: COSV50787897; COSMIC: COSV50787897; API