rs112327353

Variant names:

• chr11-95838199-G-A
• rs112327353
• NM_016156.6:c.1488C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_016156.6(MTMR2):​c.1488C>T​(p.Thr496Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,574,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MTMR2 NM_016156.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.177
• Publications: 1 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-95838199-G-A is Benign according to our data. Variant chr11-95838199-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 306539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00201 (306/152074) while in subpopulation AFR AF = 0.00681 (283/41530). AF 95% confidence interval is 0.00616. There are 0 homozygotes in GnomAd4. There are 157 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1488C>T	p.Thr496Thr	synonymous	Exon 13 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.1404C>T	p.Thr468Thr	synonymous	Exon 12 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.1395C>T	p.Thr465Thr	synonymous	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.1488C>T	p.Thr496Thr	synonymous	Exon 13 of 15	ENSP00000345752.6	Q13614-1
	MTMR2	ENST00000352297.11	TSL:1	c.1272C>T	p.Thr424Thr	synonymous	Exon 14 of 16	ENSP00000343737.7	Q13614-2
	MTMR2	ENST00000393223.8	TSL:1	c.1272C>T	p.Thr424Thr	synonymous	Exon 14 of 16	ENSP00000376915.3	Q13614-2

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000460 AC: 115 AN: 250190 AF XY: 0.000296

Gnomad AFR exome AF: 0.00641

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000205 AC: 292 AN: 1422586 Hom.: 0 Cov.: 25 AF XY: 0.000163 AC XY: 116 AN XY: 710080

African (AFR) AF: 0.00687 AC: 224 AN: 32586

American (AMR) AF: 0.000269 AC: 12 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000334 AC: 36 AN: 1076860

Other (OTH) AF: 0.000288 AC: 17 AN: 58990

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74344

African (AFR) AF: 0.00681 AC: 283 AN: 41530

American (AMR) AF: 0.00118 AC: 18 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67912

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	Charcot-Marie-Tooth disease type 4B1 (1)
-	-	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
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.2
DANN	Benign	0.75
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism

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: rs112327353; hg19: chr11-95571363; COSMIC: COSV60582034; COSMIC: COSV60582034;