rs200217946

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_017534.6(MYH2):​c.3128C>T​(p.Ser1043Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,028 control chromosomes in the GnomAD database, including 3 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: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00035 ( 3 hom. )

Consequence

MYH2
NM_017534.6 missense

Scores

11
5
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.72
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 -10 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.09905121).
BP6
Variant 17-10529471-G-A is Benign according to our data. Variant chr17-10529471-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321678.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000263 (40/152142) while in subpopulation AMR AF= 0.000917 (14/15272). AF 95% confidence interval is 0.000554. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH2NM_017534.6 linkc.3128C>T p.Ser1043Phe missense_variant Exon 25 of 40 ENST00000245503.10 NP_060004.3 Q9UKX2-1
MYH2NM_001100112.2 linkc.3128C>T p.Ser1043Phe missense_variant Exon 25 of 40 NP_001093582.1 Q9UKX2-1
MYHASNR_125367.1 linkn.168-38066G>A intron_variant Intron 2 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH2ENST00000245503.10 linkc.3128C>T p.Ser1043Phe missense_variant Exon 25 of 40 1 NM_017534.6 ENSP00000245503.5 Q9UKX2-1

Frequencies

GnomAD3 genomes
AF:
0.000263
AC:
40
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000917
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:
0.000279
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000625
AC:
157
AN:
251352
Hom.:
1
AF XY:
0.000596
AC XY:
81
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00327
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:
0.000246
Gnomad OTH exome
AF:
0.00261
GnomAD4 exome
AF:
0.000350
AC:
512
AN:
1461886
Hom.:
3
Cov.:
34
AF XY:
0.000348
AC XY:
253
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00306
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000298
Gnomad4 OTH exome
AF:
0.000695
GnomAD4 genome
AF:
0.000263
AC:
40
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000917
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.000958
Alfa
AF:
0.000315
Hom.:
0
Bravo
AF:
0.000404
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000626
AC:
76
EpiCase
AF:
0.000436
EpiControl
AF:
0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 12, 2024Variant summary: MYH2 c.3128C>T (p.Ser1043Phe) results in a non-conservative amino acid change located in the Myosin Tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251352 control chromosomes in the gnomAD database, including 1 homozygotes. To our knowledge, no occurrence of c.3128C>T in individuals affected with Myopathy, Proximal, And Ophthalmoplegia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 321678). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Inclusion Body Myopathy, Dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Myopathy, proximal, and ophthalmoplegia Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.84
.;T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.099
T;T
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.1
M;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.95
P;P
Vest4
0.76
MVP
0.98
MPC
1.1
ClinPred
0.15
T
GERP RS
5.2
Varity_R
0.79
gMVP
0.46

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: rs200217946; hg19: chr17-10432788; API