11-95923947-T-G

Variant names:

• chr11-95923947-T-G
• rs3824874
• NM_016156.6:c.8A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016156.6(MTMR2):​c.8A>C​(p.Lys3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,557,506 control chromosomes in the GnomAD database, including 103,642 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (7360 hom., cov: 33)
  • Exomes 𝑓: 0.36 (96282 hom.)
• Consequence: MTMR2 NM_016156.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.46
• Publications: 44 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)

ENSG00000295552 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020042658).
• BP6: Variant 11-95923947-T-G is Benign according to our data. Variant chr11-95923947-T-G is described in ClinVar as Benign. ClinVar VariationId is 260686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

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.8A>C	p.Lys3Thr	missense	Exon 1 of 15	NP_057240.3
	MTMR2	NM_001440647.1		c.8A>C	p.Lys3Thr	missense	Exon 1 of 14	NP_001427576.1
	MTMR2	NM_001440648.1		c.8A>C	p.Lys3Thr	missense	Exon 1 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.8A>C	p.Lys3Thr	missense	Exon 1 of 15	ENSP00000345752.6	Q13614-1
	MTMR2	ENST00000352297.11	TSL:1	c.-280A>C		5_prime_UTR	Exon 1 of 16	ENSP00000343737.7	Q13614-2
	MTMR2	ENST00000393223.8	TSL:1	c.-301A>C		5_prime_UTR	Exon 1 of 16	ENSP00000376915.3	Q13614-2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43157 AN: 152070 Hom.: 7358 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.288 AC: 46351 AN: 160886 AF XY: 0.288

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.362 AC: 509240 AN: 1405318 Hom.: 96282 Cov.: 47 AF XY: 0.357 AC XY: 247845 AN XY: 693846

African (AFR) AF: 0.101 AC: 3227 AN: 32048

American (AMR) AF: 0.220 AC: 8133 AN: 36970

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13138 AN: 25192

East Asian (EAS) AF: 0.319 AC: 11567 AN: 36224

South Asian (SAS) AF: 0.177 AC: 14144 AN: 79942

European-Finnish (FIN) AF: 0.263 AC: 12935 AN: 49166

Middle Eastern (MID) AF: 0.303 AC: 1699 AN: 5606

European-Non Finnish (NFE) AF: 0.392 AC: 423851 AN: 1081948

Other (OTH) AF: 0.353 AC: 20546 AN: 58222

GnomAD4 genome AF: 0.284 AC: 43159 AN: 152188 Hom.: 7360 Cov.: 33 AF XY: 0.275 AC XY: 20474 AN XY: 74404

African (AFR) AF: 0.109 AC: 4513 AN: 41560

American (AMR) AF: 0.272 AC: 4155 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1846 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1453 AN: 5176

South Asian (SAS) AF: 0.167 AC: 807 AN: 4824

European-Finnish (FIN) AF: 0.260 AC: 2757 AN: 10594

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26514 AN: 67944

Other (OTH) AF: 0.336 AC: 711 AN: 2114

Alfa AF: 0.349 Hom.: 16124

Bravo AF: 0.281

TwinsUK AF: 0.394 AC: 1460

ALSPAC AF: 0.395 AC: 1524

ESP6500AA AF: 0.0895 AC: 384

ESP6500EA AF: 0.317 AC: 2643

ExAC AF: 0.132 AC: 13896

Asia WGS AF: 0.227 AC: 790 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Charcot-Marie-Tooth disease type 4B1 (4)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D
Sift4G	Benign	0.13	T
Polyphen		0.039	B
Vest4		0.10
MPC		0.40
ClinPred		0.042	T
GERP RS		0.82
PromoterAI		0.0088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.40
Mutation Taster		=97/3	polymorphism (auto)

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: rs3824874; hg19: chr11-95657111; COSMIC: COSV60579185; COSMIC: COSV60579185;