8-2057765-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003970.4(MYOM2):c.545C>T(p.Thr182Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,613,924 control chromosomes in the GnomAD database, including 2,310 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.068 (469 hom., cov: 31)
  • Exomes 𝑓: 0.046 (1841 hom.)
• Consequence: MYOM2 NM_003970.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.28

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003680259).
• BP6: Variant 8-2057765-C-T is Benign according to our data. Variant chr8-2057765-C-T is described in ClinVar as [Benign]. Clinvar id is 3056138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM2	NM_003970.4	c.545C>T	p.Thr182Met	missense_variant	5/37	ENST00000262113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM2	ENST00000262113.9	c.545C>T	p.Thr182Met	missense_variant	5/37	1	NM_003970.4	P1
MYOM2	ENST00000523438.1	c.-82+12597C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10326 AN: 152030 Hom.: 469 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0581

GnomAD3 exomes AF: 0.0468 AC: 11756 AN: 251046 Hom.: 415 AF XY: 0.0449 AC XY: 6087 AN XY: 135664

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.0509

Gnomad SAS exome AF: 0.0249

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.0471

Gnomad OTH exome AF: 0.0447

GnomAD4 exome AF: 0.0461 AC: 67442 AN: 1461776 Hom.: 1841 Cov.: 35 AF XY: 0.0456 AC XY: 33133 AN XY: 727186

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0685

Gnomad4 EAS exome AF: 0.0374

Gnomad4 SAS exome AF: 0.0249

Gnomad4 FIN exome AF: 0.0323

Gnomad4 NFE exome AF: 0.0460

Gnomad4 OTH exome AF: 0.0501

GnomAD4 genome AF: 0.0679 AC: 10338 AN: 152148 Hom.: 469 Cov.: 31 AF XY: 0.0665 AC XY: 4950 AN XY: 74392

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0503

Gnomad4 ASJ AF: 0.0622

Gnomad4 EAS AF: 0.0428

Gnomad4 SAS AF: 0.0199

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.0467

Gnomad4 OTH AF: 0.0575

Alfa AF: 0.0520 Hom.: 416

Bravo AF: 0.0723

TwinsUK AF: 0.0434 AC: 161

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.133 AC: 587

ESP6500EA AF: 0.0487 AC: 419

ExAC AF: 0.0485 AC: 5889

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.0496

EpiControl AF: 0.0471

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYOM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

This variant is classified as 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	0.18
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.15	P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Vest4		0.085
MPC		0.042
ClinPred		0.031	T
GERP RS		3.7
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17064618; hg19: chr8-2005883; COSMIC: COSV50741043;