11-95836162-G-T

Position:

• chr11-95836162-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016156.6(MTMR2):​c.1756C>A​(p.Arg586Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,612,476 control chromosomes in the GnomAD database, including 1,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (158 hom., cov: 32)
  • Exomes 𝑓: 0.027 (912 hom.)
• Consequence: MTMR2 NM_016156.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-95836162-G-T is Benign according to our data. Variant chr11-95836162-G-T is described in ClinVar as [Benign]. Clinvar id is 306536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-95836162-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTMR2	NM_016156.6	c.1756C>A	p.Arg586Arg	synonymous_variant	14/15	ENST00000346299.10	NP_057240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTMR2	ENST00000346299.10	c.1756C>A	p.Arg586Arg	synonymous_variant	14/15	1	NM_016156.6	ENSP00000345752.6

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5593 AN: 151772 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.0770

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0347 AC: 8709 AN: 251076 Hom.: 286 AF XY: 0.0378 AC XY: 5134 AN XY: 135702

Gnomad AFR exome AF: 0.0540

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0903

Gnomad FIN exome AF: 0.0798

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0338

GnomAD4 exome AF: 0.0267 AC: 38934 AN: 1460586 Hom.: 912 Cov.: 32 AF XY: 0.0289 AC XY: 21019 AN XY: 726608

Gnomad4 AFR exome AF: 0.0573

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.000529

Gnomad4 SAS exome AF: 0.0907

Gnomad4 FIN exome AF: 0.0767

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0368 AC: 5589 AN: 151890 Hom.: 158 Cov.: 32 AF XY: 0.0397 AC XY: 2947 AN XY: 74248

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.0866

Gnomad4 FIN AF: 0.0770

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0232 Hom.: 32

Bravo AF: 0.0311

Asia WGS AF: 0.0330 AC: 115 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0247

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4B1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.3
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61735577; hg19: chr11-95569326;