11-95838183-C-T

Variant names:

• chr11-95838183-C-T
• rs61735578
• NM_016156.6:c.1504G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016156.6(MTMR2):​c.1504G>A​(p.Glu502Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E502Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MTMR2 NM_016156.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016156.6. 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
	MTMR2	NM_016156.6	MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 13 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.1420G>A	p.Glu474Lys	missense	Exon 12 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.1411G>A	p.Glu471Lys	missense	Exon 12 of 14	NP_001427577.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 13 of 15	ENSP00000345752.6	Q13614-1
	MTMR2	ENST00000352297.11	TSL:1	c.1288G>A	p.Glu430Lys	missense	Exon 14 of 16	ENSP00000343737.7	Q13614-2
	MTMR2	ENST00000393223.8	TSL:1	c.1288G>A	p.Glu430Lys	missense	Exon 14 of 16	ENSP00000376915.3	Q13614-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453796 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723712

African (AFR) AF: 0.00 AC: 0 AN: 33220

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105046

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.73	P
Vest4		0.66
MutPred		0.71		Gain of ubiquitination at E502 (P = 0.0185)
MVP		0.97
MPC		0.52
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.88
gMVP		0.91
Mutation Taster		=48/52	disease causing

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: rs61735578; hg19: chr11-95571347;