rs147587689

Variant names:

• chr19-40396098-C-T
• rs147587689
• NM_181882.3:c.2254G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_181882.3(PRX):​c.2254G>A​(p.Glu752Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,256 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 1.87
• Publications: 7 publications found

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), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 3

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0088068545).
• BP6: Variant 19-40396098-C-T is Benign according to our data. Variant chr19-40396098-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216834.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00176 (268/152380) while in subpopulation AMR AF = 0.00438 (67/15310). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181882.3. 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
	PRX	NM_181882.3	MANE Select	c.2254G>A	p.Glu752Lys	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.2539G>A	p.Glu847Lys	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*2459G>A		3_prime_UTR	Exon 6 of 6	NP_066007.1	Q9BXM0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRX	ENST00000324001.8	TSL:1 MANE Select	c.2254G>A	p.Glu752Lys	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*2459G>A		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.2539G>A	p.Glu847Lys	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00242

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00136 AC: 341 AN: 250762 AF XY: 0.00135

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00195 AC: 2855 AN: 1461876 Hom.: 2 Cov.: 38 AF XY: 0.00195 AC XY: 1417 AN XY: 727238

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00237 AC: 2638 AN: 1112008

Other (OTH) AF: 0.00126 AC: 76 AN: 60394

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74524

African (AFR) AF: 0.000288 AC: 12 AN: 41598

American (AMR) AF: 0.00438 AC: 67 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00214 Hom.: 5

Bravo AF: 0.00173

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Charcot-Marie-Tooth disease type 4F (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	PRX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.044
Eigen_PC	Benign	-0.0058
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.075
Sift	Benign	0.11	T
Sift4G	Uncertain	0.011	D
Polyphen		0.93	P
Vest4		0.20
MVP		0.62
MPC		0.51
ClinPred		0.015	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.19
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs147587689; hg19: chr19-40902005; COSMIC: COSV106092375;