rs139295564

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP3BP4_StrongBP6BS1

The NM_017534.6(MYH2):c.3308A>T(p.Glu1103Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,276 control chromosomes in the GnomAD database, including 1 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 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

MYH2
NM_017534.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.71

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]

MYH2 links:

ENSG00000272736 (HGNC:):

ENSG00000272736 links:

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]

MYHAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.051382124).

BP6

Variant 17-10529208-T-A is Benign according to our data. Variant chr17-10529208-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465934.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000787 (120/152394) while in subpopulation AFR AF= 0.00262 (109/41598). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6 link	c.3308A>T	p.Glu1103Val	missense_variant	Exon 26 of 40	ENST00000245503.10	NP_060004.3	Q9UKX2-1
MYH2	NM_001100112.2 link	c.3308A>T	p.Glu1103Val	missense_variant	Exon 26 of 40		NP_001093582.1	Q9UKX2-1
MYHAS	NR_125367.1 link	n.168-38329T>A		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10 link	c.3308A>T	p.Glu1103Val	missense_variant	Exon 26 of 40	1	NM_017534.6	ENSP00000245503.5		Q9UKX2-1

Frequencies

GnomAD3 genomes

AF:

0.000788

AC:

120

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000334

AC:

AN:

251330

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000174

AC:

254

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000787

AC:

120

AN:

152394

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74528

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000941

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

MYH2-related disorder

Benign:1

May 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.051

T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.7

H;H

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.98

D;D

Vest4

0.76

MVP

0.93

MPC

1.2

ClinPred

0.11

GERP RS

5.3

Varity_R

0.64

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over