chr17-10521351-C-T

Variant summary

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

The NM_017534.6(MYH2):​c.5755G>A​(p.Ala1919Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYH2
NM_017534.6 missense

Scores

13
3
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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]

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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, 0.866

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH2NM_017534.6 linkuse as main transcriptc.5755G>A p.Ala1919Thr missense_variant 40/40 ENST00000245503.10
MYHASNR_125367.1 linkuse as main transcriptn.168-46186C>T intron_variant, non_coding_transcript_variant
MYH2NM_001100112.2 linkuse as main transcriptc.5755G>A p.Ala1919Thr missense_variant 40/40

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH2ENST00000245503.10 linkuse as main transcriptc.5755G>A p.Ala1919Thr missense_variant 40/401 NM_017534.6 P1Q9UKX2-1
ENST00000399342.6 linkuse as main transcriptn.207-11973C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251458
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135896
show subpopulations
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 testingInvitaeSep 02, 2020This sequence change replaces alanine with threonine at codon 1919 of the MYH2 protein (p.Ala1919Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.56
.;D;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;.;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
4.4
.;H;H;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.54
N;D;D;.
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Benign
0.32
T;D;D;T
Polyphen
1.0
.;D;D;.
Vest4
0.76
MutPred
0.73
.;Gain of phosphorylation at A1919 (P = 0.099);Gain of phosphorylation at A1919 (P = 0.099);.;
MVP
0.95
MPC
1.1
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.47
gMVP
0.23

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: rs1464949119; hg19: chr17-10424668; API