8-2052291-G-C

Variant names:

• chr8-2052291-G-C
• rs35985218
• NM_003970.4:c.241G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003970.4(MYOM2):​c.241G>C​(p.Glu81Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E81K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYOM2 NM_003970.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.42
• Publications: 10 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14298493).

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>C	p.Glu81Gln	missense	Exon 3 of 37	NP_003961.3	P54296

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM2	ENST00000262113.9	TSL:1 MANE Select	c.241G>C	p.Glu81Gln	missense	Exon 3 of 37	ENSP00000262113.4	P54296
	MYOM2	ENST00000887732.1		c.241G>C	p.Glu81Gln	missense	Exon 3 of 38	ENSP00000557791.1
	MYOM2	ENST00000887733.1		c.241G>C	p.Glu81Gln	missense	Exon 3 of 38	ENSP00000557792.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245550 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453188 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722048

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 43736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108026

Other (OTH) AF: 0.00 AC: 0 AN: 59962

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 58

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	0.98
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.057
Sift	Benign	0.31	T
Sift4G	Benign	0.15	T
Vest4		0.32
MutPred		0.41		Loss of solvent accessibility (P = 0.0013)
MVP		0.69
MPC		0.0086
ClinPred		0.10	T
GERP RS		3.8
gMVP		0.27
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs35985218; hg19: chr8-2000409;