chr17-10521326-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2PP3BP4_StrongBP6_Very_StrongBS2

The NM_017534.6(MYH2):​c.5780G>A​(p.Arg1927Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,614,124 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1927R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 32)
Exomes 𝑓: 0.0064 ( 46 hom. )

Consequence

MYH2
NM_017534.6 missense

Scores

7
6
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

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
Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when AlphaMissense, max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.011096537).
BP6
Variant 17-10521326-C-T is Benign according to our data. Variant chr17-10521326-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAd4 at 6 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH2NM_017534.6 linkuse as main transcriptc.5780G>A p.Arg1927Gln missense_variant 40/40 ENST00000245503.10
MYHASNR_125367.1 linkuse as main transcriptn.168-46211C>T intron_variant, non_coding_transcript_variant
MYH2NM_001100112.2 linkuse as main transcriptc.5780G>A p.Arg1927Gln missense_variant 40/40

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH2ENST00000245503.10 linkuse as main transcriptc.5780G>A p.Arg1927Gln missense_variant 40/401 NM_017534.6 P1Q9UKX2-1
ENST00000399342.6 linkuse as main transcriptn.207-11998C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00446
AC:
679
AN:
152164
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00121
Gnomad AMI
AF:
0.0471
Gnomad AMR
AF:
0.00530
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.00330
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00651
Gnomad OTH
AF:
0.00525
GnomAD3 exomes
AF:
0.00410
AC:
1031
AN:
251444
Hom.:
7
AF XY:
0.00445
AC XY:
605
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00243
Gnomad ASJ exome
AF:
0.000893
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00307
Gnomad FIN exome
AF:
0.00236
Gnomad NFE exome
AF:
0.00653
Gnomad OTH exome
AF:
0.00489
GnomAD4 exome
AF:
0.00644
AC:
9421
AN:
1461842
Hom.:
46
Cov.:
31
AF XY:
0.00629
AC XY:
4574
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000956
Gnomad4 AMR exome
AF:
0.00293
Gnomad4 ASJ exome
AF:
0.000880
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00333
Gnomad4 FIN exome
AF:
0.00303
Gnomad4 NFE exome
AF:
0.00757
Gnomad4 OTH exome
AF:
0.00596
GnomAD4 genome
AF:
0.00446
AC:
679
AN:
152282
Hom.:
6
Cov.:
32
AF XY:
0.00403
AC XY:
300
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00120
Gnomad4 AMR
AF:
0.00530
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.00330
Gnomad4 NFE
AF:
0.00651
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00600
Hom.:
1
Bravo
AF:
0.00466
TwinsUK
AF:
0.00863
AC:
32
ALSPAC
AF:
0.00701
AC:
27
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00744
AC:
64
ExAC
AF:
0.00415
AC:
504
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.00687
EpiControl
AF:
0.00735

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024MYH2: BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 23, 2020This variant is associated with the following publications: (PMID: 15741996) -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsNov 07, 2016- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 15, 2014- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 07, 2020- -
MYH2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 09, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Myopathy, proximal, and ophthalmoplegia Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.50
.;D;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;.;D;D
MetaRNN
Benign
0.011
T;T;T;T
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
4.3
.;H;H;.
MutationTaster
Benign
0.92
D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.50
N;D;D;.
REVEL
Uncertain
0.51
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Benign
1.0
T;D;D;T
Polyphen
1.0
.;D;D;.
Vest4
0.81
MVP
0.98
MPC
1.0
ClinPred
0.15
T
GERP RS
5.5
Varity_R
0.37
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: rs34161789; hg19: chr17-10424643; COSMIC: COSV55450500; COSMIC: COSV55450500; API