ENST00000395938.7:c.531A>C

Variant names:

Variant summary

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

The ENST00000395938.7(PMP22):c.531A>C(p.Lys177Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,583,870 control chromosomes in the GnomAD database, including 212,586 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25172 hom., cov: 33)

Exomes 𝑓: 0.51 ( 187414 hom. )

Consequence

PMP22
ENST00000395938.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.18

Publications

28 publications found

Variant links:

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PMP22 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 1A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)
hereditary neuropathy with liability to pressure palsies
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 1E
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PMP22 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 (BayesDel_noAF=-0.7).

BP6

Variant 17-15230858-T-G is Benign according to our data. Variant chr17-15230858-T-G is described in ClinVar as Benign. ClinVar VariationId is 321859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395938.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMP22	NM_000304.4	MANE Select	c.*59A>C	3_prime_UTR	Exon 5 of 5	NP_000295.1	Q01453
PMP22	NM_001281455.2		c.*59A>C	3_prime_UTR	Exon 5 of 5	NP_001268384.1	Q6FH25
PMP22	NM_001281456.2		c.*59A>C	3_prime_UTR	Exon 5 of 5	NP_001268385.1	Q01453

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMP22	ENST00000395938.7	TSL:1	c.531A>C	p.Lys177Asn	missense	Exon 5 of 5	ENSP00000379269.3	A0A6Q8PF08
PMP22	ENST00000312280.9	TSL:1 MANE Select	c.*59A>C		3_prime_UTR	Exon 5 of 5	ENSP00000308937.3	Q01453
PMP22	ENST00000494511.7	TSL:1	c.*59A>C		3_prime_UTR	Exon 3 of 3	ENSP00000462782.2	J3KT36

Frequencies

GnomAD3 genomes

AF:

0.567

AC:

86180

AN:

151982

Hom.:

25125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.637

Gnomad AMR

AF:

0.552

Gnomad ASJ

AF:

0.558

Gnomad EAS

AF:

0.614

Gnomad SAS

AF:

0.536

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.501

Gnomad OTH

AF:

0.550

GnomAD2 exomes

AF:

0.528

AC:

129815

AN:

245660

AF XY:

0.524

show subpopulations

Gnomad AFR exome

AF:

0.730

Gnomad AMR exome

AF:

0.527

Gnomad ASJ exome

AF:

0.556

Gnomad EAS exome

AF:

0.610

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.504

Gnomad OTH exome

AF:

0.529

GnomAD4 exome

AF:

0.509

AC:

729236

AN:

1431770

Hom.:

187414

Cov.:

AF XY:

0.510

AC XY:

363677

AN XY:

713456

show subpopulations

African (AFR)

AF:

0.729

AC:

23976

AN:

32902

American (AMR)

AF:

0.532

AC:

23720

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

14430

AN:

25958

East Asian (EAS)

AF:

0.633

AC:

25009

AN:

39532

South Asian (SAS)

AF:

0.524

AC:

44798

AN:

85564

European-Finnish (FIN)

AF:

0.427

AC:

21857

AN:

51146

Middle Eastern (MID)

AF:

0.601

AC:

3380

AN:

5622

European-Non Finnish (NFE)

AF:

0.498

AC:

540979

AN:

1087084

Other (OTH)

AF:

0.524

AC:

31087

AN:

59382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

17551

35102

52654

70205

87756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15870

31740

47610

63480

79350

<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:

0.567

AC:

86280

AN:

152100

Hom.:

25172

Cov.:

AF XY:

0.564

AC XY:

41925

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.715

AC:

29685

AN:

41500

American (AMR)

AF:

0.551

AC:

8422

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.558

AC:

1938

AN:

3472

East Asian (EAS)

AF:

0.615

AC:

3167

AN:

5148

South Asian (SAS)

AF:

0.537

AC:

2584

AN:

4816

European-Finnish (FIN)

AF:

0.427

AC:

4517

AN:

10568

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.501

AC:

34042

AN:

67992

Other (OTH)

AF:

0.554

AC:

1169

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1887

3774

5661

7548

9435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

730

1460

2190

2920

3650

<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:

0.533

Hom.:

39081

Bravo

AF:

0.583

Asia WGS

AF:

0.581

AC:

2016

AN:

3478

EpiCase

AF:

0.513

EpiControl

AF:

0.509

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease, type I (2)

not provided (2)

not specified (2)

Charcot-Marie-Tooth disease (1)

Hereditary liability to pressure palsies (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.0

(source)

DANN

Benign

0.82

PhyloP100

1.2

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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