rs141498429

Variant names:

• chr11-95888155-CCCT-C
• rs141498429
• NM_016156.6:c.184_186delAGG

Your query was ambiguous. Multiple possible variants found:

• chr11-95888155-CCCT-C
• chr11-95888155-CCCT-CCCTCCT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM4_Supporting PP3_Moderate BP6 BS1 BS2

The ENST00000346299.10(MTMR2):​c.184_186delAGG​(p.Arg62del) variant causes a conservative inframe deletion, splice region change. The variant allele was found at a frequency of 0.000463 in 1,581,962 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: MTMR2 ENST00000346299.10 conservative_inframe_deletion, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

MTMR2 (HGNC:7450): (myotubularin related protein 2) This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

MTMR2 Gene-Disease associations (from GenCC):

• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4B1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000346299.10. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-95888155-CCCT-C is Benign according to our data. Variant chr11-95888155-CCCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 306547.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00223 (334/150026) while in subpopulation AFR AF = 0.0075 (311/41454). AF 95% confidence interval is 0.00682. There are 3 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000346299.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	NM_016156.6	MANE Select	c.184_186delAGG	p.Arg62del	conservative_inframe_deletion splice_region	Exon 2 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.184_186delAGG	p.Arg62del	conservative_inframe_deletion splice_region	Exon 2 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.184_186delAGG	p.Arg62del	conservative_inframe_deletion splice_region	Exon 2 of 14	NP_001427577.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.184_186delAGG	p.Arg62del	conservative_inframe_deletion splice_region	Exon 2 of 15	ENSP00000345752.6
	MTMR2	ENST00000352297.11	TSL:1	c.-33_-31delAGG		splice_region	Exon 3 of 16	ENSP00000343737.7
	MTMR2	ENST00000393223.8	TSL:1	c.-33_-31delAGG		splice_region	Exon 3 of 16	ENSP00000376915.3

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 333 AN: 149908 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.000629 AC: 157 AN: 249596 AF XY: 0.000534

Gnomad AFR exome AF: 0.00684

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000279 AC: 399 AN: 1431936 Hom.: 2 AF XY: 0.000262 AC XY: 187 AN XY: 713086

African (AFR) AF: 0.00675 AC: 224 AN: 33174

American (AMR) AF: 0.000561 AC: 25 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50136

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5692

European-Non Finnish (NFE) AF: 0.0000993 AC: 108 AN: 1087500

Other (OTH) AF: 0.000455 AC: 27 AN: 59326

GnomAD4 genome AF: 0.00223 AC: 334 AN: 150026 Hom.: 3 Cov.: 32 AF XY: 0.00202 AC XY: 148 AN XY: 73210

African (AFR) AF: 0.00750 AC: 311 AN: 41454

American (AMR) AF: 0.000197 AC: 3 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9820

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000150 AC: 10 AN: 66788

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.000418 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Charcot-Marie-Tooth disease type 4 (2)
-	-	2	Charcot-Marie-Tooth disease type 4B1 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MTMR2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: 4
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141498429; hg19: chr11-95621319;