chr19-40397766-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181882.3(PRX):c.586C>G(p.Arg196Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,414,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict 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. R196Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PRX
NM_181882.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.340

Publications

7 publications found

Variant links:

Genes affected

PRX (HGNC:13797): (periaxin) This gene encodes a protein involved in peripheral nerve myelin upkeep. The encoded protein contains 2 PDZ domains which were named after PSD95 (post synaptic density protein), DlgA (Drosophila disc large tumor suppressor), and ZO1 (a mammalian tight junction protein). Two alternatively spliced transcript variants have been described for this gene which encode different protein isoforms and which are targeted differently in the Schwann cell. Mutations in this gene cause Charcot-Marie-Tooth neuoropathy, type 4F and Dejerine-Sottas neuropathy. [provided by RefSeq, Jul 2008]

PRX Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 4
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 4F
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Charcot-Marie-Tooth disease type 3
Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

PRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3 link	c.586C>G	p.Arg196Gly	missense_variant	Exon 7 of 7	ENST00000324001.8	NP_870998.2	Q9BXM0-1
PRX	NM_001411127.1 link	c.871C>G	p.Arg291Gly	missense_variant	Exon 7 of 7		NP_001398056.1
PRX	XM_017027047.2 link	c.484C>G	p.Arg162Gly	missense_variant	Exon 4 of 4		XP_016882536.1
PRX	NM_020956.2 link	c.*791C>G		3_prime_UTR_variant	Exon 6 of 6		NP_066007.1	Q9BXM0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8 link	c.586C>G	p.Arg196Gly	missense_variant	Exon 7 of 7	1	NM_181882.3	ENSP00000326018.6		Q9BXM0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

166418

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1414802

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

699472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32900

American (AMR)

AF:

0.00

AC:

AN:

36812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

37998

South Asian (SAS)

AF:

0.00

AC:

AN:

80958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1088798

Other (OTH)

AF:

0.00

AC:

AN:

58672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 4

Uncertain:1

Feb 15, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with PRX-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine with glycine at codon 196 of the PRX protein (p.Arg196Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.77

M_CAP

Benign

0.0099

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

0.34

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.6

REVEL

Benign

0.14

Sift

Benign

0.12

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.60

MutPred

0.42

Loss of MoRF binding (P = 0.0188);

MVP

0.47

MPC

0.53

ClinPred

0.83

GERP RS

1.1

Varity_R

0.12

gMVP

0.55

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over