chr17-10529983-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_017534.6(MYH2):ā€‹c.2789A>Gā€‹(p.Glu930Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 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 (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MYH2
NM_017534.6 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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, 0.885

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH2NM_017534.6 linkuse as main transcriptc.2789A>G p.Glu930Gly missense_variant 23/40 ENST00000245503.10 NP_060004.3
MYHASNR_125367.1 linkuse as main transcriptn.168-37554T>C intron_variant, non_coding_transcript_variant
MYH2NM_001100112.2 linkuse as main transcriptc.2789A>G p.Glu930Gly missense_variant 23/40 NP_001093582.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH2ENST00000245503.10 linkuse as main transcriptc.2789A>G p.Glu930Gly missense_variant 23/401 NM_017534.6 ENSP00000245503 P1Q9UKX2-1
ENST00000399342.6 linkuse as main transcriptn.207-3341T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461788
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2017In 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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 930 of the MYH2 protein (p.Glu930Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
D;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
.;D
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.7
D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.028
D;D
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.44
Gain of methylation at R931 (P = 0.0367);Gain of methylation at R931 (P = 0.0367);
MVP
0.98
MPC
1.4
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.65
gMVP
0.45

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1335748239; hg19: chr17-10433300; API