NM_181882.3:c.2655T>C

Variant names:

• chr19-40395697-A-G
• rs268672
• NM_181882.3:c.2655T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_181882.3(PRX):​c.2655T>C​(p.Pro885Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,490 control chromosomes in the GnomAD database, including 230,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27124 hom., cov: 33)
  • Exomes 𝑓: 0.52 (203248 hom.)
• Consequence: PRX NM_181882.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.17
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-40395697-A-G is Benign according to our data. Variant chr19-40395697-A-G is described in ClinVar as Benign. ClinVar VariationId is 130049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

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.2655T>C	p.Pro885Pro	synonymous	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.2940T>C	p.Pro980Pro	synonymous	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*2860T>C		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.2655T>C	p.Pro885Pro	synonymous	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*2860T>C		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.2940T>C	p.Pro980Pro	synonymous	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87698 AN: 151590 Hom.: 27082 Cov.: 33

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.552

GnomAD2 exomes AF: 0.500 AC: 125454 AN: 250912 AF XY: 0.495

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.495

GnomAD4 exome AF: 0.521 AC: 762106 AN: 1461782 Hom.: 203248 Cov.: 94 AF XY: 0.519 AC XY: 377289 AN XY: 727194

African (AFR) AF: 0.801 AC: 26818 AN: 33478

American (AMR) AF: 0.519 AC: 23200 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12087 AN: 26136

East Asian (EAS) AF: 0.184 AC: 7305 AN: 39696

South Asian (SAS) AF: 0.472 AC: 40681 AN: 86254

European-Finnish (FIN) AF: 0.450 AC: 24038 AN: 53404

Middle Eastern (MID) AF: 0.450 AC: 2586 AN: 5748

European-Non Finnish (NFE) AF: 0.534 AC: 594334 AN: 1111962

Other (OTH) AF: 0.514 AC: 31057 AN: 60388

GnomAD4 genome AF: 0.579 AC: 87787 AN: 151708 Hom.: 27124 Cov.: 33 AF XY: 0.569 AC XY: 42172 AN XY: 74120

African (AFR) AF: 0.800 AC: 33104 AN: 41372

American (AMR) AF: 0.517 AC: 7894 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1548 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1035 AN: 5140

South Asian (SAS) AF: 0.467 AC: 2251 AN: 4820

European-Finnish (FIN) AF: 0.445 AC: 4671 AN: 10500

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35412 AN: 67836

Other (OTH) AF: 0.544 AC: 1151 AN: 2114

Alfa AF: 0.528 Hom.: 30767

Bravo AF: 0.596

Asia WGS AF: 0.337 AC: 1173 AN: 3478

EpiCase AF: 0.509

EpiControl AF: 0.522

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Charcot-Marie-Tooth disease type 4F (3)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Dejerine-Sottas disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.14
DANN	Benign	0.31
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs268672; hg19: chr19-40901604; COSMIC: COSV52530165;