rs186380748

Variant names:

• chr11-95857602-G-C
• rs186380748
• NM_016156.6:c.604C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016156.6(MTMR2):​c.604C>G​(p.Pro202Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000278 in 1,612,234 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: MTMR2 NM_016156.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.68
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.119524926).

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.604C>G	p.Pro202Ala	missense	Exon 7 of 15	NP_057240.3
	MTMR2	NM_001440648.1		c.604C>G	p.Pro202Ala	missense	Exon 7 of 14	NP_001427577.1
	MTMR2	NM_001440650.1		c.604C>G	p.Pro202Ala	missense	Exon 7 of 14	NP_001427579.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTMR2	ENST00000346299.10	TSL:1 MANE Select	c.604C>G	p.Pro202Ala	missense	Exon 7 of 15	ENSP00000345752.6	Q13614-1
	MTMR2	ENST00000352297.11	TSL:1	c.388C>G	p.Pro130Ala	missense	Exon 8 of 16	ENSP00000343737.7	Q13614-2
	MTMR2	ENST00000393223.8	TSL:1	c.388C>G	p.Pro130Ala	missense	Exon 8 of 16	ENSP00000376915.3	Q13614-2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151758 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000248 AC: 62 AN: 250368 AF XY: 0.000310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000289 AC: 422 AN: 1460358 Hom.: 1 Cov.: 29 AF XY: 0.000307 AC XY: 223 AN XY: 726584

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.000224 AC: 10 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86190

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53372

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5742

European-Non Finnish (NFE) AF: 0.000323 AC: 359 AN: 1110912

Other (OTH) AF: 0.000199 AC: 12 AN: 60338

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151876 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74240

African (AFR) AF: 0.0000725 AC: 3 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000382

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Charcot-Marie-Tooth disease (1)
-	1	-	Charcot-Marie-Tooth disease type 4 (1)
-	1	-	Charcot-Marie-Tooth disease type 4B1 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.0068
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.87
MPC		0.32
ClinPred		0.078	T
GERP RS		3.6
Varity_R		0.34
gMVP		0.63
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186380748; hg19: chr11-95590766;