rs558018

Positions:

• chr11-95836284-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016156.6(MTMR2):​c.1634A>G​(p.Asn545Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,612,936 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (40 hom.)
• Consequence: MTMR2 NM_016156.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0088483095).
• BP6: Variant 11-95836284-T-C is Benign according to our data. Variant chr11-95836284-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 194416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-95836284-T-C is described in Lovd as [Benign]. Variant chr11-95836284-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.012 (1824/152082) while in subpopulation AFR AF= 0.0425 (1763/41518). AF 95% confidence interval is 0.0408. There are 35 homozygotes in gnomad4. There are 866 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTMR2	NM_016156.6	c.1634A>G	p.Asn545Ser	missense_variant	14/15	ENST00000346299.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTMR2	ENST00000346299.10	c.1634A>G	p.Asn545Ser	missense_variant	14/15	1	NM_016156.6	P3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1820 AN: 151964 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00293 AC: 734 AN: 250808 Hom.: 12 AF XY: 0.00199 AC XY: 269 AN XY: 135516

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00124 AC: 1805 AN: 1460854 Hom.: 40 Cov.: 32 AF XY: 0.00108 AC XY: 782 AN XY: 726724

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.0120 AC: 1824 AN: 152082 Hom.: 35 Cov.: 32 AF XY: 0.0116 AC XY: 866 AN XY: 74372

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00219 Hom.: 7

Bravo AF: 0.0135

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0388 AC: 171

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MTMR2: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -

Charcot-Marie-Tooth disease type 4B1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Charcot-Marie-Tooth disease type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.;.;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;.;.;D
MetaRNN	Benign	0.0088	T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.037	D;D;D;D;D
Sift4G	Benign	0.096	T;T;T;T;.
Polyphen		0.38	B;.;.;.;.
Vest4		0.78
MVP		0.89
MPC		0.34
ClinPred		0.12	T
GERP RS		5.8
Varity_R		0.28
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs558018; hg19: chr11-95569448;