rs755446743

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4_SupportingPP5BS2

The NM_000530.8(MPZ):c.706_708delAAG(p.Lys236del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000217 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K236K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MPZ
NM_000530.8 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2O:1

Conservation

PhyloP100: 5.69

Publications

5 publications found

Variant links:

Genes affected

MPZ (HGNC:7225): (myelin protein zero) This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major structural protein of the peripheral myelin sheath. The encoded protein contains a large hydrophobic extracellular domain and a smaller basic intracellular domain, which are essential for the formation and stabilization of the multilamellar structure of the compact myelin. Mutations in this gene are associated with autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B) and other polyneuropathies, such as Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN). A recent study showed that two isoforms are produced from the same mRNA by use of alternative in-frame translation termination codons via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2015]

MPZ Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
neuropathy, congenital hypomyelinating, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease dominant intermediate D
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2J
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MPZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000530.8. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-161305914-CCTT-C is Pathogenic according to our data. Variant chr1-161305914-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447734.

BS2

High AC in GnomAdExome4 at 34 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000530.8. 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
	MPZ	NM_000530.8	MANE Select	c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	NP_001302420.1	A0A5F9ZI26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPZ	ENST00000533357.5	TSL:1 MANE Select	c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	ENSP00000432943.1	P25189-1
MPZ	ENST00000463290.5	TSL:1	n.706_708delAAG		non_coding_transcript_exon	Exon 6 of 7	ENSP00000431538.1	P25189-1
MPZ	ENST00000672602.2		c.706_708delAAG	p.Lys236del	conservative_inframe_deletion	Exon 6 of 6	ENSP00000500814.2	A0A5F9ZI26

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249906

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461562

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111946

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000658

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Charcot-Marie-Tooth disease (3)

Charcot-Marie-Tooth disease type 1B (1)

Charcot-Marie-Tooth disease type 2I (1)

Charcot-Marie-Tooth disease, type I (1)

Dejerine-Sottas disease (1)

Inborn genetic diseases (1)

Dejerine-Sottas disease;C0270912:Charcot-Marie-Tooth disease type 1B;C0393818:Congenital hypomyelinating neuropathy;C1843153:Charcot-Marie-Tooth disease type 2J (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=42/58

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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