Genetic Variant PLXNC1:p.Asn86Lys (chr12-94149229-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_005761.3(PLXNC1):c.258C>A(p.Asn86Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PLXNC1
NM_005761.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.88

Publications

0 publications found

Variant links:

Genes affected

PLXNC1 (HGNC:9106): (plexin C1) This gene encodes a member of the plexin family. Plexins are transmembrane receptors for semaphorins, a large family of proteins that regulate axon guidance, cell motility and migration, and the immune response. The encoded protein and its ligand regulate melanocyte adhesion, and viral semaphorins may modulate the immune response by binding to this receptor. The encoded protein may be a tumor suppressor protein for melanoma. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jan 2011]

PLXNC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity PLXC1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24727559).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005761.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNC1	NM_005761.3	MANE Select	c.258C>A	p.Asn86Lys	missense	Exon 1 of 31	NP_005752.1	O60486

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNC1	ENST00000258526.9	TSL:1 MANE Select	c.258C>A	p.Asn86Lys	missense	Exon 1 of 31	ENSP00000258526.4	O60486

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707756

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29460

American (AMR)

AF:

0.00

AC:

AN:

40930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24904

East Asian (EAS)

AF:

0.00

AC:

AN:

35274

South Asian (SAS)

AF:

0.00

AC:

AN:

82476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46932

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098156

Other (OTH)

AF:

0.00

AC:

AN:

58844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.97

PhyloP100

2.9

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.29

REVEL

Benign

0.19

Sift

Benign

0.061

Sift4G

Benign

0.92

Polyphen

0.49

Vest4

0.33

MutPred

0.40

Gain of methylation at N86 (P = 0.0014)

MVP

0.36

MPC

1.9

ClinPred

0.75

GERP RS

4.5

Varity_R

0.46

gMVP

0.19

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over