8-2057473-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003970.4(MYOM2):c.389C>G(p.Ala130Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,613,986 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: MYOM2 NM_003970.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.919

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011306375).
• BP6: Variant 8-2057473-C-G is Benign according to our data. Variant chr8-2057473-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2658306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-2057473-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM2	NM_003970.4	c.389C>G	p.Ala130Gly	missense_variant	4/37	ENST00000262113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM2	ENST00000262113.9	c.389C>G	p.Ala130Gly	missense_variant	4/37	1	NM_003970.4	P1
MYOM2	ENST00000523438.1	c.-82+12305C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152170 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 250556 Hom.: 0 AF XY: 0.00104 AC XY: 141 AN XY: 135530

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00130 AC: 1907 AN: 1461698 Hom.: 3 Cov.: 71 AF XY: 0.00127 AC XY: 924 AN XY: 727148

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152288 Hom.: 1 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74468

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00105

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.00185

EpiControl AF: 0.00190

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

MYOM2: BP4, BS2 -

MYOM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.036
Sift	Benign	0.22	T
Sift4G	Benign	0.14	T
Vest4		0.26
MVP		0.33
MPC		0.0084
ClinPred		0.0038	T
GERP RS		2.7
gMVP		0.34

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: rs138240288; hg19: chr8-2005591;