chr17-10392944-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002472.3(MYH8):c.5350C>G(p.Arg1784Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00729 in 1,614,100 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1784W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 59 hom. )

Consequence

MYH8
NM_002472.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.467

Publications

9 publications found

Variant links:

Genes affected

MYH8 (HGNC:7578): (myosin heavy chain 8) 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 predominantly expressed in fetal skeletal muscle. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in trismus-pseudocamptodactyly syndrome. [provided by RefSeq, Sep 2009]

MYH8 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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03230071).

BP6

Variant 17-10392944-G-C is Benign according to our data. Variant chr17-10392944-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211567.

BS2

High AC in GnomAd4 at 709 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002472.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH8	NM_002472.3	MANE Select	c.5350C>G	p.Arg1784Gly	missense	Exon 37 of 40	NP_002463.2
	MYHAS	NR_125367.1		n.76+9737G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH8	ENST00000403437.2	TSL:5 MANE Select	c.5350C>G	p.Arg1784Gly	missense	Exon 37 of 40	ENSP00000384330.2
MYHAS	ENST00000399342.6	TSL:3	n.76+9737G>C		intron	N/A
MYHAS	ENST00000581304.2	TSL:3	n.52+9737G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00467

AC:

711

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00750

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00530

AC:

1334

AN:

251490

AF XY:

0.00547

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00513

Gnomad NFE exome

AF:

0.00764

Gnomad OTH exome

AF:

0.00717

GnomAD4 exome

AF:

0.00756

AC:

11058

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00740

AC XY:

5384

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33480

American (AMR)

AF:

0.00183

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00386

AC:

101

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00596

AC:

514

AN:

86258

European-Finnish (FIN)

AF:

0.00569

AC:

304

AN:

53418

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00860

AC:

9561

AN:

1112012

Other (OTH)

AF:

0.00732

AC:

442

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

815

1629

2444

3258

4073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00466

AC:

709

AN:

152208

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41520

American (AMR)

AF:

0.00307

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00686

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00750

AC:

510

AN:

68010

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00281

Hom.:

Bravo

AF:

0.00412

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00604

AC:

733

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 16, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29565416)

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH8: PP3, BS2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Mar 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hecht syndrome

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Mar 31, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on data from the NHLBI Exome Sequencing Project (ESP), the G-allele has an overall frequency of approximately 0.42% (45/10754) total alleles studied. The G-allele was observed in 0.58% (41/7016) European American alleles and in 0.11% (4/3738) African American alleles studied and was not observed in the homozygous state out of 5377 individuals studied. Based on data from the 1000 Genomes Project, the G-allele has an overall frequency of approximately 0.32% (7/2188) and the highest frequency was in 1.82% (2/110) 1.82% Puerto Rican chromosomes studied.The R1784 amino acid is highly conserved among available vertebrate species.This alteration is predicted to be probably damaging with a score of 0.961 (sensitivity: 0.62; specificity: 0.92)This alteration is predicted to be deleterious with a score of 0.000 (conservation: 3.05)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

0.0054

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.032

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

3.1

PhyloP100

0.47

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.86

MVP

0.82

MPC

0.82

ClinPred

0.032

GERP RS

3.0

Varity_R

0.66

gMVP

0.85

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over