rs268671

Variant names:

• chr19-40395707-A-G
• rs268671
• NM_181882.3:c.2645T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-40395707-A-G
• chr19-40395707-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181882.3(PRX):​c.2645T>C​(p.Val882Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,456 control chromosomes in the GnomAD database, including 229,976 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V882V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.58 (27096 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202880 hom.)
• Consequence: PRX NM_181882.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.561
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.21127E-7).
• BP6: Variant 19-40395707-A-G is Benign according to our data. Variant chr19-40395707-A-G is described in ClinVar as Benign. ClinVar VariationId is 130048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 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.2645T>C	p.Val882Ala	missense	Exon 7 of 7	NP_870998.2	Q9BXM0-1
	PRX	NM_001411127.1		c.2930T>C	p.Val977Ala	missense	Exon 7 of 7	NP_001398056.1	A0A669KBF1
	PRX	NM_020956.2		c.*2850T>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.2645T>C	p.Val882Ala	missense	Exon 7 of 7	ENSP00000326018.6	Q9BXM0-1
	PRX	ENST00000291825.11	TSL:1	c.*2850T>C		3_prime_UTR	Exon 6 of 6	ENSP00000291825.6	Q9BXM0-2
	PRX	ENST00000674005.2		c.2930T>C	p.Val977Ala	missense	Exon 7 of 7	ENSP00000501261.1	A0A669KBF1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87645 AN: 151538 Hom.: 27054 Cov.: 33

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.500 AC: 125436 AN: 250946 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: 0.494

GnomAD4 exome AF: 0.521 AC: 761420 AN: 1461798 Hom.: 202880 Cov.: 97 AF XY: 0.518 AC XY: 376955 AN XY: 727192

African (AFR) AF: 0.801 AC: 26818 AN: 33480

American (AMR) AF: 0.519 AC: 23194 AN: 44714

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

East Asian (EAS) AF: 0.184 AC: 7307 AN: 39698

South Asian (SAS) AF: 0.472 AC: 40685 AN: 86254

European-Finnish (FIN) AF: 0.450 AC: 24037 AN: 53406

Middle Eastern (MID) AF: 0.450 AC: 2584 AN: 5746

European-Non Finnish (NFE) AF: 0.534 AC: 593668 AN: 1111976

Other (OTH) AF: 0.514 AC: 31040 AN: 60388

GnomAD4 genome AF: 0.578 AC: 87734 AN: 151658 Hom.: 27096 Cov.: 33 AF XY: 0.569 AC XY: 42154 AN XY: 74116

African (AFR) AF: 0.800 AC: 33100 AN: 41372

American (AMR) AF: 0.518 AC: 7900 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1546 AN: 3464

East Asian (EAS) AF: 0.202 AC: 1036 AN: 5140

South Asian (SAS) AF: 0.467 AC: 2255 AN: 4826

European-Finnish (FIN) AF: 0.445 AC: 4668 AN: 10482

Middle Eastern (MID) AF: 0.445 AC: 130 AN: 292

European-Non Finnish (NFE) AF: 0.521 AC: 35364 AN: 67816

Other (OTH) AF: 0.543 AC: 1146 AN: 2110

Alfa AF: 0.537 Hom.: 14616

Bravo AF: 0.596

TwinsUK AF: 0.536 AC: 1987

ALSPAC AF: 0.533 AC: 2055

ESP6500AA AF: 0.789 AC: 3477

ESP6500EA AF: 0.518 AC: 4453

ExAC AF: 0.507 AC: 61551

Asia WGS AF: 0.337 AC: 1174 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
-	-	5	not specified (5)
-	-	2	Charcot-Marie-Tooth disease type 4F (2)
-	-	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
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.42
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00075	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.56
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.046
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.27
ClinPred		0.0091	T
GERP RS		2.7
Varity_R		0.018
gMVP		0.096
Mutation Taster		=98/2	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: rs268671; hg19: chr19-40901614; COSMIC: COSV52530169;