Genetic Variant NM_003970.4:c.241G>A (chr8-2052291-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003970.4(MYOM2):c.241G>A(p.Glu81Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,605,502 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.012 ( 16 hom., cov: 33)

Exomes 𝑓: 0.015 ( 232 hom. )

Consequence

MYOM2
NM_003970.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.42

Publications

10 publications found

Variant links:

Genes affected

MYOM2 (HGNC:7614): (myomesin 2) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD and 165 kD. The predicted MYOM2 protein contains 1,465 amino acids. Like MYOM1, MYOM2 has a unique N-terminal domain followed by 12 repeat domains with strong homology to either fibronectin type III or immunoglobulin C2 domains. Protein sequence comparisons suggested that the MYOM2 protein and bovine M protein are identical. [provided by RefSeq, Jul 2008]

MYOM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039822757).

BP6

Variant 8-2052291-G-A is Benign according to our data. Variant chr8-2052291-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056560.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1803/152332) while in subpopulation SAS AF = 0.0286 (138/4826). AF 95% confidence interval is 0.0247. There are 16 homozygotes in GnomAd4. There are 927 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003970.4. 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
	MYOM2	NM_003970.4	MANE Select	c.241G>A	p.Glu81Lys	missense	Exon 3 of 37	NP_003961.3	P54296

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYOM2	ENST00000262113.9	TSL:1 MANE Select	c.241G>A	p.Glu81Lys	missense	Exon 3 of 37	ENSP00000262113.4	P54296
MYOM2	ENST00000887732.1		c.241G>A	p.Glu81Lys	missense	Exon 3 of 38	ENSP00000557791.1
MYOM2	ENST00000887733.1		c.241G>A	p.Glu81Lys	missense	Exon 3 of 38	ENSP00000557792.1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1800

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0241

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0159

AC:

3898

AN:

245550

AF XY:

0.0175

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.00624

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0151

AC:

21919

AN:

1453170

Hom.:

232

Cov.:

AF XY:

0.0157

AC XY:

11309

AN XY:

722034

show subpopulations

African (AFR)

AF:

0.00259

AC:

AN:

33248

American (AMR)

AF:

0.00670

AC:

293

AN:

43736

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

491

AN:

25950

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39458

South Asian (SAS)

AF:

0.0334

AC:

2833

AN:

84848

European-Finnish (FIN)

AF:

0.0234

AC:

1246

AN:

53360

Middle Eastern (MID)

AF:

0.0242

AC:

111

AN:

4596

European-Non Finnish (NFE)

AF:

0.0144

AC:

15913

AN:

1108012

Other (OTH)

AF:

0.0157

AC:

944

AN:

59962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1199

2398

3598

4797

5996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0118

AC:

1803

AN:

152332

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

927

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00216

AC:

AN:

41592

American (AMR)

AF:

0.00706

AC:

108

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4826

European-Finnish (FIN)

AF:

0.0241

AC:

256

AN:

10624

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1103

AN:

68026

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

192

287

383

479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.00925

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0163

AC:

1974

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MYOM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.61

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

PhyloP100

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.75

REVEL

Benign

0.077

Sift

Benign

0.46

Sift4G

Benign

0.26

Vest4

0.47

MPC

0.0076

ClinPred

0.011

GERP RS

3.8

gMVP

0.29

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over