chr17-10533312-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017534.6(MYH2):ā€‹c.2414T>Cā€‹(p.Val805Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00049 ( 0 hom., cov: 32)
Exomes š‘“: 0.00039 ( 5 hom. )

Consequence

MYH2
NM_017534.6 missense

Scores

5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 1.58
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]
MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011940777).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000487 (74/152052) while in subpopulation EAS AF= 0.0127 (66/5180). AF 95% confidence interval is 0.0103. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH2NM_017534.6 linkc.2414T>C p.Val805Ala missense_variant Exon 21 of 40 ENST00000245503.10 NP_060004.3 Q9UKX2-1
MYH2NM_001100112.2 linkc.2414T>C p.Val805Ala missense_variant Exon 21 of 40 NP_001093582.1 Q9UKX2-1
MYHASNR_125367.1 linkn.168-34225A>G intron_variant Intron 2 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH2ENST00000245503.10 linkc.2414T>C p.Val805Ala missense_variant Exon 21 of 40 1 NM_017534.6 ENSP00000245503.5 Q9UKX2-1

Frequencies

GnomAD3 genomes
AF:
0.000487
AC:
74
AN:
151934
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0127
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000748
AC:
188
AN:
251434
Hom.:
2
AF XY:
0.000648
AC XY:
88
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0102
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000388
AC:
567
AN:
1461832
Hom.:
5
Cov.:
31
AF XY:
0.000355
AC XY:
258
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0125
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00116
GnomAD4 genome
AF:
0.000487
AC:
74
AN:
152052
Hom.:
0
Cov.:
32
AF XY:
0.000498
AC XY:
37
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0127
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000562
Hom.:
1
Bravo
AF:
0.000484
ExAC
AF:
0.000807
AC:
98
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Pathogenic:1Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely pathogenic, flagged submissionreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2025- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 11, 2024BS1 -
Benign, criteria provided, single submitterclinical testingGeneDxAug 29, 2019This variant is associated with the following publications: (PMID: 22349865, 27066573) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1.1% East Asian ExAC, 2 homozygotes, not in ClinVar. Cai 2011 reported the variant in 3/21 Jpanese patients with inclusion body myositis. Clinical features of IBM include adult-onset weakness of proximal or distal muscle and normal or slightly elevated serum creatine kinase (CK) level. This variant has not been associated with myopathy ith external ophthalmoplegia. Therefore, despite of the classification of the variant, I do not think the disease meets criteria for reporting in BabySeq. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T;T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.70
.;T
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-2.1
N;N
REVEL
Uncertain
0.32
Sift
Benign
0.048
D;D
Sift4G
Benign
0.67
T;T
Polyphen
0.0020
B;B
Vest4
0.82
MVP
0.70
MPC
0.82
ClinPred
0.080
T
GERP RS
5.2
Varity_R
0.15
gMVP
0.44

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: rs200662973; hg19: chr17-10436629; COSMIC: COSV55431069; API