8-2052291-G-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.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. 13/18 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 0.012 (16 hom., cov: 33)
  • Exomes 𝑓: 0.015 (232 hom.)
• Consequence: MYOM2 NM_003970.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.42

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=0.0039822757).
• BP6: Variant 8-2052291-G-A is Benign according to our data. Variant chr8-2052291-G-A is described in ClinVar as [Benign]. Clinvar id is 3056560.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-2052291-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM2	NM_003970.4	c.241G>A	p.Glu81Lys	missense_variant	3/37	ENST00000262113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM2	ENST00000262113.9	c.241G>A	p.Glu81Lys	missense_variant	3/37	1	NM_003970.4	P1
MYOM2	ENST00000523438.1	c.-82+7123G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1800 AN: 152214 Hom.: 16 Cov.: 33

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

GnomAD3 exomes AF: 0.0159 AC: 3898 AN: 245550 Hom.: 39 AF XY: 0.0175 AC XY: 2329 AN XY: 132720

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 SAS exome AF: 0.0350

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.: 31 AF XY: 0.0157 AC XY: 11309 AN XY: 722034

Gnomad4 AFR exome AF: 0.00259

Gnomad4 AMR exome AF: 0.00670

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.0234

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0118 AC: 1803 AN: 152332 Hom.: 16 Cov.: 33 AF XY: 0.0124 AC XY: 927 AN XY: 74478

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0141 Hom.: 23

Bravo AF: 0.00925

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0185 AC: 159

ExAC AF: 0.0163 AC: 1974

Asia WGS AF: 0.0110 AC: 39 AN: 3478

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	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Uncertain	1.0
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.61	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.077
Sift	Benign	0.46	T
Sift4G	Benign	0.26	T
Vest4		0.47
MPC		0.0076
ClinPred		0.011	T
GERP RS		3.8
gMVP		0.29

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: rs35985218; hg19: chr8-2000409;