rs268666

Variant names:

• chr19-40412258-C-T
• rs268666
• NM_181882.3:c.-243+1080G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181882.3(PRX):​c.-243+1080G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,966 control chromosomes in the GnomAD database, including 26,706 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (26706 hom., cov: 32)
• Consequence: PRX NM_181882.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.569
• Publications: 5 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), Orphanet, Ambry Genetics
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRX	NM_181882.3	c.-243+1080G>A		intron_variant	Intron 1 of 6	ENST00000324001.8	NP_870998.2
PRX	NM_001411127.1	c.43+2442G>A		intron_variant	Intron 1 of 6		NP_001398056.1
PRX	NM_020956.2	c.-243+1080G>A		intron_variant	Intron 1 of 5		NP_066007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRX	ENST00000324001.8	c.-243+1080G>A		intron_variant	Intron 1 of 6	1	NM_181882.3	ENSP00000326018.6

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86935 AN: 151850 Hom.: 26669 Cov.: 32

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.682

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.551

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.573 AC: 87019 AN: 151966 Hom.: 26706 Cov.: 32 AF XY: 0.563 AC XY: 41821 AN XY: 74290

African (AFR) AF: 0.793 AC: 32844 AN: 41436

American (AMR) AF: 0.516 AC: 7884 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1569 AN: 3468

East Asian (EAS) AF: 0.162 AC: 838 AN: 5172

South Asian (SAS) AF: 0.479 AC: 2308 AN: 4818

European-Finnish (FIN) AF: 0.450 AC: 4750 AN: 10554

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34934 AN: 67940

Other (OTH) AF: 0.544 AC: 1146 AN: 2108

Alfa AF: 0.550 Hom.: 7948

Bravo AF: 0.589

Asia WGS AF: 0.325 AC: 1132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.5
DANN	Benign	0.56
PhyloP100		0.57
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs268666; hg19: chr19-40918165;