17-10526786-C-A

Position:

• chr17-10526786-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017534.6(MYH2):​c.4000G>T​(p.Ala1334Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1334T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.90

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH2. . Gene score misZ 1.9724 (greater than the threshold 3.09). Trascript score misZ 4.733 (greater than threshold 3.09). GenCC has associacion of gene with childhood-onset autosomal recessive myopathy with external ophthalmoplegia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, myopathy, proximal, and ophthalmoplegia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH2	NM_017534.6	c.4000G>T	p.Ala1334Ser	missense_variant	30/40	ENST00000245503.10
MYHAS	NR_125367.1	n.168-40751C>A		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.4000G>T	p.Ala1334Ser	missense_variant	30/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH2	ENST00000245503.10	c.4000G>T	p.Ala1334Ser	missense_variant	30/40	1	NM_017534.6	P1
	ENST00000399342.6	n.207-6538C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251330 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 12, 2017	This sequence change replaces alanine with serine at codon 1334 of the MYH2 protein (p.Ala1334Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs779257410, ExAC 0.001%). This variant has not been reported in the literature in individuals with a MYH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MYH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 03, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.83	P;P
Vest4		0.65
MutPred		0.37		Gain of phosphorylation at A1334 (P = 0.0463);Gain of phosphorylation at A1334 (P = 0.0463);
MVP		0.86
MPC		0.39
ClinPred		0.76	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779257410; hg19: chr17-10430103;