chr19-40396335-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001411127.1(PRX):c.2302A>G(p.Met768Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00555 in 1,605,988 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M768T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.032 ( 238 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 211 hom. )

Consequence

PRX
NM_001411127.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.360

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017869473).

BP6

Variant 19-40396335-T-C is Benign according to our data. Variant chr19-40396335-T-C is described in ClinVar as Benign. ClinVar VariationId is 329270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001411127.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	NM_181882.3	MANE Select	c.2017A>G	p.Met673Val	missense	Exon 7 of 7	NP_870998.2
PRX	NM_001411127.1		c.2302A>G	p.Met768Val	missense	Exon 7 of 7	NP_001398056.1
PRX	NM_020956.2		c.*2222A>G		3_prime_UTR	Exon 6 of 6	NP_066007.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRX	ENST00000324001.8	TSL:1 MANE Select	c.2017A>G	p.Met673Val	missense	Exon 7 of 7	ENSP00000326018.6
PRX	ENST00000291825.11	TSL:1	c.*2222A>G		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6
PRX	ENST00000674005.2		c.2302A>G	p.Met768Val	missense	Exon 7 of 7	ENSP00000501261.1

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4546

AN:

144162

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00946

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000664

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.000347

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.00779

AC:

1957

AN:

251120

AF XY:

0.00591

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00298

AC:

4356

AN:

1461702

Hom.:

211

Cov.:

AF XY:

0.00256

AC XY:

1862

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.105

AC:

3523

AN:

33460

American (AMR)

AF:

0.00512

AC:

229

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000116

AC:

129

AN:

1111912

Other (OTH)

AF:

0.00709

AC:

428

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

325

650

975

1300

1625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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

AF:

0.0316

AC:

4553

AN:

144286

Hom.:

238

Cov.:

AF XY:

0.0300

AC XY:

2109

AN XY:

70236

show subpopulations

African (AFR)

AF:

0.113

AC:

4350

AN:

38426

American (AMR)

AF:

0.00945

AC:

136

AN:

14392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3406

East Asian (EAS)

AF:

0.00

AC:

AN:

4774

South Asian (SAS)

AF:

0.000664

AC:

AN:

4518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9492

Middle Eastern (MID)

AF:

0.00893

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.000348

AC:

AN:

66186

Other (OTH)

AF:

0.0194

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

188

376

563

751

939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0111

Hom.:

155

Bravo

AF:

0.0336

ESP6500AA

AF:

0.109

AC:

480

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00974

AC:

1183

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease type 4 (1)

Charcot-Marie-Tooth disease type 4F (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.5

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.12

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.79

PhyloP100

-0.36

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.080

REVEL

Benign

0.038

Sift

Benign

0.54

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.19

MVP

0.18

MPC

0.23

ClinPred

0.0011

GERP RS

0.78

Varity_R

0.084

gMVP

0.21

Mutation Taster

=97/3

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over