8-2050864-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003970.4(MYOM2):c.98C>A(p.Ala33Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0215 in 1,607,738 control chromosomes in the GnomAD database, including 434 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (43 hom., cov: 33)
  • Exomes 𝑓: 0.022 (391 hom.)
• Consequence: MYOM2 NM_003970.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.91

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=0.0036394894).
• BP6: Variant 8-2050864-C-A is Benign according to our data. Variant chr8-2050864-C-A is described in ClinVar as [Benign]. Clinvar id is 3060228.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-2050864-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2735/152278) while in subpopulation NFE AF= 0.0239 (1624/68016). AF 95% confidence interval is 0.0229. There are 43 homozygotes in gnomad4. There are 1346 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM2	NM_003970.4	c.98C>A	p.Ala33Glu	missense_variant	2/37	ENST00000262113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM2	ENST00000262113.9	c.98C>A	p.Ala33Glu	missense_variant	2/37	1	NM_003970.4	P1
MYOM2	ENST00000523438.1	c.-82+5696C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2736 AN: 152160 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0180 AC: 4509 AN: 251052 Hom.: 61 AF XY: 0.0184 AC XY: 2502 AN XY: 135700

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0347

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00906

Gnomad FIN exome AF: 0.0305

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0218 AC: 31769 AN: 1455460 Hom.: 391 Cov.: 30 AF XY: 0.0215 AC XY: 15556 AN XY: 722986

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0360

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00954

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0180 AC: 2735 AN: 152278 Hom.: 43 Cov.: 33 AF XY: 0.0181 AC XY: 1346 AN XY: 74468

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0179 Hom.: 30

Bravo AF: 0.0167

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0234 AC: 201

ExAC AF: 0.0170 AC: 2062

EpiCase AF: 0.0242

EpiControl AF: 0.0233

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

May 30, 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.12
Sift	Uncertain	0.011	D
Sift4G	Benign	0.57	T
Vest4		0.63
MPC		0.015
ClinPred		0.024	T
GERP RS		4.9
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs35578989; hg19: chr8-1998978;