chr17-10529185-G-T

Position:

• chr17-10529185-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_017534.6(MYH2):​c.3331C>A​(p.Gln1111Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH2 NM_017534.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.61

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH2	NM_017534.6	c.3331C>A	p.Gln1111Lys	missense_variant	26/40	ENST00000245503.10	NP_060004.3
MYHAS	NR_125367.1	n.168-38352G>T		intron_variant, non_coding_transcript_variant
MYH2	NM_001100112.2	c.3331C>A	p.Gln1111Lys	missense_variant	26/40		NP_001093582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.3331C>A	p.Gln1111Lys	missense_variant	26/40	1	NM_017534.6	ENSP00000245503	P1
	ENST00000399342.6	n.207-4139G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251318 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135850

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: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2022

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1111 of the MYH2 protein (p.Gln1111Lys). This variant is present in population databases (rs758264018, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.56		Gain of ubiquitination at Q1111 (P = 0.023);Gain of ubiquitination at Q1111 (P = 0.023);
MVP		0.91
MPC		1.2
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.36

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: rs758264018; hg19: chr17-10432502;